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Ji M, Ran X, Zuo H, Zhang Q. Novel Insights into the Kallikrein-Kinin System in Fulminant Myocarditis: Physiological Basis and Potential Therapeutic Advances. J Inflamm Res 2024; 17:7347-7360. [PMID: 39429854 PMCID: PMC11490248 DOI: 10.2147/jir.s488237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024] Open
Abstract
Fulminant myocarditis (FM) is characterized by rapid cardiac deterioration often instigated by an inflammatory cytokine storm. The kallikrein-kinin system (KKS) is a metabolic cascade known for releasing vasoactive kinins, such as bradykinin-related peptides, possessing diverse pharmacological activities that include inflammation, regulation of vascular permeability, endothelial barrier dysfunction, and blood pressure modulation. The type 1 and type 2 bradykinin receptors (B1R and B2R), integral components of the KKS system, mediate the primary biological effects of kinin peptides. This review aims to offer a comprehensive overview of the primary mechanisms of the KKS in FM, including an examination of the structural components, regulatory activation, and downstream signaling pathways of the KKS. Furthermore, it explores the involvement of the tissue kallikrein/B1R/inducible nitric oxide synthase (TK/B1R/iNOS) pathway in myocyte dysfunction, modulation of the immune response, and preservation of endothelial barrier integrity. The potential therapeutic advances targeting the inhibition of the KKS in managing FM will be discussed, providing valuable insights for the development of clinical treatment strategies.
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Affiliation(s)
- Mengmeng Ji
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Xiao Ran
- Department of Critical-Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Houjuan Zuo
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Qin Zhang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
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Abstract
Activation of arginine–vasopressin is one of the hormonal responses to face vasodilation-related hypotension. Released from the post-pituitary gland, vasopressin induces vasoconstriction through the activation of V1a receptors located on vascular smooth muscle cells. Due to its non-selective receptor affinity arginine–vasopressin also activates V2 (located on renal tubular cells of collecting ducts) and V1b (located in the anterior pituitary and in the pancreas) receptors, thereby potentially promoting undesired side effects such as anti-diuresis, procoagulant properties due to release of the von Willebrand’s factor and platelet activation. Finally, it also cross-activates oxytocin receptors. During septic shock, vasopressin plasma levels were reported to be lower than expected, and a hypersensitivity to its vasopressor effect is reported in such situation. Terlipressin and selepressin are synthetic vasopressin analogues with a higher affinity for the V1 receptor, and, hence, potentially less side effects. In this narrative review, we present the current knowledge of the rationale, benefits and risks of vasopressin use in the setting of septic shock and vasoplegic shock following cardiac surgery. Clearly, vasopressin administration allows reducing norepinephrine requirements, but so far, no improvement of survival was reported and side effects are frequent, particularly ischaemic events. Finally, we will discuss the current indications for vasopressin and its agonists in the setting of septic shock, and the remaining unresolved questions.
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Alipoor E, Mohammad Hosseinzadeh F, Hosseinzadeh-Attar MJ. Adipokines in critical illness: A review of the evidence and knowledge gaps. Biomed Pharmacother 2018; 108:1739-1750. [PMID: 30372877 DOI: 10.1016/j.biopha.2018.09.165] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/27/2018] [Accepted: 09/28/2018] [Indexed: 12/28/2022] Open
Abstract
Adipose tissue products or adipokines play a major role in chronic endocrine and metabolic disorders; however, little is known about critical conditions. In this article, the experimental and clinical evidence of alterations of adipokines, adiponectin, leptin, resistin, visfatin, asymmetric dimethylarginine (ADMA), and ghrelin in critical illness, their potential metabolic, diagnostic, and prognostic value, and the gaps in the field have been reviewed. The results showed considerable changes in the concentration of the adipokines; while the impact of adipokines on metabolic disorders such as insulin resistance and inflammation has not been well documented in critically ill patients. There is no consensus about the circulatory and functional changes of leptin and adiponectin. However, it seems that lower concentrations of adiponectin at admission with gradual consequent increase might be a useful pattern in determining better outcomes of critical illness. Some evidence has suggested the adverse effects of elevated resistin concentration, potential prognostic importance of visfatin, and therapeutic value of ghrelin. High ADMA levels and low arginine:ADMA ratio were also proposed as predictors of ICU mortality and morbidities. However, there is no consensus on these findings. Although primary data indicated the role of adipokines in critical illness, further studies are required to clarify whether the reason of these changes is pathophysiological or compensatory. The relationship of pathophysiological background, disease severity, baseline nutritional status and nutrition support during hospitalization, and variations in body fat percentage and distribution with adipokines, as well as the potential prognostic or therapeutic role of these peptides should be further investigated in critically ill patients.
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Affiliation(s)
- Elham Alipoor
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran; Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohammad Hosseinzadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Hosseinzadeh-Attar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia.
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Myocardial Microcirculation and Mitochondrial Energetics in the Isolated Rat Heart. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 876:159-165. [PMID: 26782208 DOI: 10.1007/978-1-4939-3023-4_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Normal functioning of myocardium requires adequate oxygenation, which in turn is dependent on an adequate microcirculation. NADH-fluorimetry enables a direct evaluation of the adequacy of tissue oxygenation while the measurement of quenching of Pd-porphyrine (PpIX) phosphorescence enables quantitative measurement of microvascular pO2. Combination of these two techniques provides information about the relation between microvascular oxygen content and parenchymal oxygen availability in Langendorff hearts. In normal myocardium there is heterogeneity at the microcirculatory level resulting in the existence of microcirculatory weak units, originating at the capillary level, which reoxygenate the slowest upon reoxygenation after an episode of ischemia. Sepsis and myocardial hypertrophia alter the pattern of oxygen transport whereby the microcirculation is disturbed at the arteriolar/arterial level. NADH fluorimetry also reveals a disturbance of mitochondrial oxygen availability in sepsis. Furthermore it is shown that these techniques can also be applied to various organs and tissues in vivo.
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5
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Ince C, Mik EG. Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol (1985) 2016; 120:226-35. [DOI: 10.1152/japplphysiol.00298.2015] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 06/05/2015] [Indexed: 12/23/2022] Open
Abstract
After shock, persistent oxygen extraction deficit despite the apparent adequate recovery of systemic hemodynamic and oxygen-derived variables has been a source of uncertainty and controversy. Dysfunction of oxygen transport pathways during intensive care underlies the sequelae that lead to organ failure, and the limitations of techniques used to measure tissue oxygenation in vivo have contributed to the lack of progress in this area. Novel techniques have provided detailed quantitative insight into the determinants of microcirculatory and mitochondrial oxygenation. These techniques, which are based on the oxygen-dependent quenching of phosphorescence or delayed luminescence are briefly reviewed. The application of these techniques to animal models of shock and resuscitation revealed the heterogeneous nature of oxygen distributions and the alterations in oxygen distribution in the microcirculation and in mitochondria. These studies identified functional shunting in the microcirculation as an underlying cause of oxygen extraction deficit observed in states of shock and resuscitation. The translation of these concepts to the bedside has been enabled by our development and clinical introduction of hand-held microscopy. This tool facilitates the direct observation of the microcirculation and its alterations at the bedside under the conditions of shock and resuscitation. Studies identified loss of coherence between the macrocirculation and the microcirculation, in which resuscitation successfully restored systemic circulation but did not alleviate microcirculatory perfusion alterations. Various mechanisms responsible for these alterations underlie the loss of hemodynamic coherence during unsuccessful resuscitation procedures. Therapeutic resolution of persistent heterogeneous microcirculatory alterations is expected to improve outcomes in critically ill patients.
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Affiliation(s)
- Can Ince
- Department of Intensive Care, Erasmus MC, University Medical Center, Rotterdam
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Egbert G. Mik
- Department of Intensive Care, Erasmus MC, University Medical Center, Rotterdam
- Department of Anesthesiology, Erasmus MC, University Medical Center, Rotterdam; and
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Thoonen R, Cauwels A, Decaluwe K, Geschka S, Tainsh RE, Delanghe J, Hochepied T, De Cauwer L, Rogge E, Voet S, Sips P, Karas RH, Bloch KD, Vuylsteke M, Stasch JP, Van de Voorde J, Buys ES, Brouckaert P. Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice. Nat Commun 2015; 6:8482. [PMID: 26442659 PMCID: PMC4699393 DOI: 10.1038/ncomms9482] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 08/27/2015] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators. Haem-free, NO-insensitive soluble guanylate cyclase (apo-sGC) generated during oxidative stress contributes to cardiovascular pathology. By generating and characterizing apo-sGC knock-in mice, Thoonen et al. provide a scientific ground for the therapeutic concept of sGC activators, and dissect the relevance of the NO-sGC axis.
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Affiliation(s)
- Robrecht Thoonen
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Anje Cauwels
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Kelly Decaluwe
- Department of Pharmacology, Ghent University, B-9000 Ghent, Belgium
| | - Sandra Geschka
- Cardiovascular Research, Bayer Pharma AG, D-42096 Wuppertal, Germany
| | - Robert E Tainsh
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA
| | - Joris Delanghe
- Department of Clinical Biology, Ghent University Hospital, B-9000 Ghent, Belgium
| | - Tino Hochepied
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Lode De Cauwer
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Elke Rogge
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Sofie Voet
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Patrick Sips
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
| | - Richard H Karas
- Molecular Cardiology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston Massachusetts 02111, USA
| | - Kenneth D Bloch
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA
| | - Marnik Vuylsteke
- Department of Plant Systems Biology, VIB, B-9052 Ghent, Belgium.,Department of Plant Biotechnology and Genetics, Ghent University, B-9052 Ghent, Belgium
| | - Johannes-Peter Stasch
- Cardiovascular Research, Bayer Pharma AG, D-42096 Wuppertal, Germany.,Department of Pharmacology, The School of Pharmacy, Martin-Luther-University, Halle, Germany
| | | | - Emmanuel S Buys
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA
| | - Peter Brouckaert
- Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium
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Ferrigno A, Di Pasqua LG, Berardo C, Richelmi P, Vairetti M. Liver plays a central role in asymmetric dimethylarginine-mediated organ injury. World J Gastroenterol 2015; 21:5131-5137. [PMID: 25954086 PMCID: PMC4419053 DOI: 10.3748/wjg.v21.i17.5131] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/24/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.
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8
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Testing a conceptual model on early opening of the microcirculation in severe sepsis and septic shock. Eur J Anaesthesiol 2015; 32:189-98. [DOI: 10.1097/eja.0000000000000126] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis*. Crit Care Med 2015; 42:2482-92. [PMID: 25080051 DOI: 10.1097/ccm.0000000000000549] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Sepsis treatment guidelines recommend macrocirculatory hemodynamic optimization; however, microcirculatory dysfunction is integral to sepsis pathogenesis. We aimed to test the hypothesis that following macrocirculatory optimization, inhaled nitric oxide would improve microcirculation in patients with sepsis and that improved microcirculation would improve lactate clearance and multiple organ dysfunction. DESIGN Randomized, sham-controlled clinical trial. SETTING Single urban academic medical center. PATIENTS Adult patients with severe sepsis and systolic blood pressure less than 90 mm Hg despite intravascular volume expansion and/or serum lactate greater than or equal to 4.0 mmol/L. INTERVENTIONS After achievement of macrocirculatory resuscitation goals, we randomized patients to 6 hours of inhaled nitric oxide (40 ppm) or sham inhaled nitric oxide administration. We administered study drug via a specialized delivery device that concealed treatment allocation so that investigators and clinical staff remained blinded. MEASUREMENTS AND MAIN RESULTS We performed sidestream dark-field videomicroscopy of the sublingual microcirculation prior to and 2 hours after study drug initiation. The primary outcome measure was the change in microcirculatory flow index. Secondary outcomes were lactate clearance and change in Sequential Organ Failure Assessment score. We enrolled 50 patients (28 of 50 [56%] requiring vasopressor agents; 15 of 50 [30%] died). Although inhaled nitric oxide significantly raised plasma nitrite levels, it did not improve microcirculatory flow, lactate clearance, or organ dysfunction. In contrast to previous studies conducted during the earliest phase of resuscitation, we found no association between changes in microcirculatory flow and lactate clearance or organ dysfunction. CONCLUSIONS Following macrocirculatory optimization, inhaled nitric oxide at 40 ppm did not augment microcirculatory perfusion in patients with sepsis. Further, we found no association between microcirculatory perfusion and multiple organ dysfunction after initial resuscitation.
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Oki M, Jesmin S, Islam MM, Mowa CN, Khatun T, Shimojo N, Sakuramoto H, Kamiyama J, Kawano S, Miyauchi T, Mizutani T. Dual blockade of endothelin action exacerbates up-regulated VEGF angiogenic signaling in the heart of lipopolysaccharide-induced endotoxemic rat model. Life Sci 2014; 118:364-9. [PMID: 24548632 DOI: 10.1016/j.lfs.2014.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 01/25/2014] [Accepted: 02/06/2014] [Indexed: 01/08/2023]
Abstract
AIMS Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it. MAIN METHODS Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed. KEY FINDINGS Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group. SIGNIFICANCE We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart.
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Affiliation(s)
- Masami Oki
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Subrina Jesmin
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Md Majedul Islam
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | | | - Tanzila Khatun
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Nobutake Shimojo
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hideaki Sakuramoto
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Junko Kamiyama
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Satoru Kawano
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Takashi Miyauchi
- Centre for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Taro Mizutani
- Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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De Cruz SJ, Kenyon NJ, Sandrock CE. Bench-to-bedside review: the role of nitric oxide in sepsis. Expert Rev Respir Med 2014; 3:511-21. [DOI: 10.1586/ers.09.39] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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12
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Santiago HC, Gonzalez Lombana CZ, Macedo JP, Utsch L, Tafuri WL, Campagnole-Santos MJ, Alves RO, Alves-Filho JCF, Romanha AJ, Cunha FQ, Teixeira MM, Radi R, Vieira LQ. NADPH phagocyte oxidase knockout mice control Trypanosoma cruzi proliferation, but develop circulatory collapse and succumb to infection. PLoS Negl Trop Dis 2012; 6:e1492. [PMID: 22348160 PMCID: PMC3279332 DOI: 10.1371/journal.pntd.0001492] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 12/09/2011] [Indexed: 01/09/2023] Open
Abstract
(•)NO is considered to be a key macrophage-derived cytotoxic effector during Trypanosoma cruzi infection. On the other hand, the microbicidal properties of reactive oxygen species (ROS) are well recognized, but little importance has been attributed to them during in vivo infection with T. cruzi. In order to investigate the role of ROS in T. cruzi infection, mice deficient in NADPH phagocyte oxidase (gp91(phox) (-/-) or phox KO) were infected with Y strain of T. cruzi and the course of infection was followed. phox KO mice had similar parasitemia, similar tissue parasitism and similar levels of IFN-γ and TNF in serum and spleen cell culture supernatants, when compared to wild-type controls. However, all phox KO mice succumbed to infection between day 15 and 21 after inoculation with the parasite, while 60% of wild-type mice were alive 50 days after infection. Further investigation demonstrated increased serum levels of nitrite and nitrate (NOx) at day 15 of infection in phox KO animals, associated with a drop in blood pressure. Treatment with a NOS2 inhibitor corrected the blood pressure, implicating NOS2 in this phenomenon. We postulate that superoxide reacts with (•)NO in vivo, preventing blood pressure drops in wild type mice. Hence, whilst superoxide from phagocytes did not play a critical role in parasite control in the phox KO animals, its production would have an important protective effect against blood pressure decline during infection with T. cruzi.
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Affiliation(s)
- Helton C. Santiago
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Claudia Z. Gonzalez Lombana
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Juan P. Macedo
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Lara Utsch
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Wagner L. Tafuri
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria José Campagnole-Santos
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Rosana O. Alves
- Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - José C. F. Alves-Filho
- Departmento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
| | - Alvaro J. Romanha
- Centro de Pesquisas René Rachou, Fiocruz, Belo Horizonte, Minas Gerais, Brazil
| | - Fernando Queiroz Cunha
- Departmento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
| | - Mauro M. Teixeira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Rafael Radi
- Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay
- Center for Free Radical and Biomedical Research, Universidad de la República, Montevideo, Uruguay
| | - Leda Q. Vieira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- * E-mail:
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Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients. Br J Nutr 2011; 107:1458-65. [PMID: 22129964 DOI: 10.1017/s0007114511004648] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In shock, organ perfusion is of vital importance because organ oxygenation is at risk. NO, the main endothelial-derived vasodilator, is crucial for organ perfusion and coronary patency. The availability of NO might depend on the balance between a substrate (arginine) and an inhibitor (asymmetric dimethylarginine; ADMA) of NO synthase. Therefore, we investigated the relationship of arginine, ADMA and their ratio with circulatory markers, disease severity, organ failure and mortality in shock patients. In forty-four patients with shock (cardiogenic n 17, septic n 27), we prospectively measured plasma arginine and ADMA at intensive care unit admission, Acute Physiology and Chronic Health Evaluation (APACHE) II-(predicted mortality) and Sequential Organ Failure Assessment (SOFA) score, and circulatory markers to investigate their relationship. Arginine concentration was decreased (34·6 (SD 17·9) μmol/l) while ADMA concentration was within the normal range (0·46 (SD 0·18) μmol/l), resulting in a decrease in the arginine:ADMA ratio. The ratio correlated with several circulatory markers (cardiac index, disseminated intravascular coagulation, bicarbonate, lactate and pH), APACHE II and SOFA score, creatine kinase and glucose. The arginine:ADMA ratio showed an association (OR 0·976, 95 % CI 0·963, 0·997, P = 0·025) and a diagnostic accuracy (area under the curve 0·721, 95 % CI 0·560, 0·882, P = 0·016) for hospital mortality, whereas the arginine or ADMA concentration alone or APACHE II-predicted mortality failed to do so. In conclusion, in shock patients, the imbalance of arginine and ADMA is related to circulatory failure, organ failure and disease severity, and predicts mortality. We propose a pathophysiological mechanism in shock: the imbalance of arginine and ADMA contributes to endothelial and cardiac dysfunction resulting in poor organ perfusion and organ failure, thereby increasing the risk of death.
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Visser M, Paulus WJ, Vermeulen MAR, Richir MC, Davids M, Wisselink W, de Mol BAJM, van Leeuwen PAM. The role of asymmetric dimethylarginine and arginine in the failing heart and its vasculature. Eur J Heart Fail 2010; 12:1274-81. [PMID: 20923854 DOI: 10.1093/eurjhf/hfq158] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability.
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Affiliation(s)
- Marlieke Visser
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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Richir M, Ellger B, Teerlink T, Siroen M, Visser M, Spreeuwenberg M, Girbes A, van der Hoven B, van den Berghe G, Wilhelm A, de Vries T, van Leeuwen P. The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients. Pharmacol Res 2009; 60:519-24. [DOI: 10.1016/j.phrs.2009.06.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2009] [Revised: 06/16/2009] [Accepted: 06/16/2009] [Indexed: 11/25/2022]
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Buys ES, Cauwels A, Raher MJ, Passeri JJ, Hobai I, Cawley SM, Rauwerdink KM, Thibault H, Sips PY, Thoonen R, Scherrer-Crosbie M, Ichinose F, Brouckaert P, Bloch KD. sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol Heart Circ Physiol 2009; 297:H654-63. [PMID: 19502556 DOI: 10.1152/ajpheart.00367.2009] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGC(alpha)(1)-deficient (sGC(alpha)(1)(-/-)) mice to unequivocally determine the role of sGC(alpha)(1)beta(1) in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGC(alpha)(1)(-/-) mice on the C57BL/6 background (sGC(alpha)(1)(-/-B6) mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGC(alpha)(1)(-/-B6) than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca(2+) handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGC(alpha)(1)(-/-B6) than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGC(alpha)(1)(-/-B6) compared with WT mice. Together, these findings suggest that cGMP generated by sGC(alpha)(1)beta(1) protects against cardiac dysfunction and mortality in murine inflammatory shock models.
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Affiliation(s)
- Emmanuel S Buys
- Department of Anesthesia and Critical Care, Cardiology Division, Anesthesia Center for Critical Care Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
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Katada K, Bihari A, Badhwar A, Yoshida N, Yoshikawa T, Potter RF, Cepinskas G. Hindlimb ischemia/reperfusion-induced remote injury to the small intestine: role of inducible nitric-oxide synthase-derived nitric oxide. J Pharmacol Exp Ther 2009; 329:919-27. [PMID: 19270191 DOI: 10.1124/jpet.108.148460] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Systemic inflammatory response syndrome, as a consequence of ischemia/reperfusion (I/R), negatively influences the function of the affected organs. The objective of this study was to assess the role of nitric oxide (NO) in remote intestinal inflammatory response elicited by hindlimb I/R. To this end, C57BL/6 (wild type; WT) and inducible nitric-oxide synthase (iNOS)-deficient mice were subjected to bilateral hindlimb ischemia (1 h) followed by 6 h of reperfusion. Some WT mice were injected with iNOS inhibitor N-[3-(aminomethyl)benzyl] acetamidine (1400W) (5 mg/kg s.c.) immediately before reperfusion, and proinflammatory response was assessed 6 h later. Hindlimb I/R resulted in dysfunction of the small intestine as assessed by the increase in permeability [blood-to-lumen clearance of Texas Red-dextran (molecular mass 3 kDa)] and an increase in the luminal levels of tumor necrosis factor (TNF)-alpha protein and nitrate/nitrite (NO(2)(-)/NO(3)(-)). The above-mentioned changes were accompanied by up-regulation of the proinflammatory phenotype in the mucosa of small intestine with respect to 1) an increase in TNF-alpha and iNOS protein expression, 2) leukocyte accumulation, 3) formation of edema, 4) an increase in leukocyte rolling/adhesion in the submucosal microvasculature, and 5) activation of transcription factor nuclear factor-kappaB and up-regulation of adhesion molecule expression. Interestingly, the most profound changes with respect to intestinal dysfunction were found in jejunum and ileum, whereas duodenum was affected the least. Interfering with iNOS activity (1400W and iNOS-deficient mice) significantly attenuated hindlimb I/R-induced inflammatory response and dysfunction of the small intestine with respect to the above-mentioned markers of inflammation. The obtained results indicate that hindlimb I/R induces remote inflammatory response in the small intestine through an iNOS-derived NO-dependent mechanism.
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Affiliation(s)
- Kazuhiro Katada
- The Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 4G5, Canada
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Staphylococcus aureus α-toxin and Escherichia coli hemolysin impair cardiac regional perfusion and contractile function by activating myocardial eicosanoid metabolism in isolated rat hearts. Crit Care Med 2009; 37:2025-32. [DOI: 10.1097/ccm.0b013e31819fff00] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Sermsappasuk P, Abdelrahman O, Weiss M. Cardiac Pharmacokinetics and Inotropic Response of Verapamil in Rats With Endotoxemia. J Pharm Sci 2008; 97:2798-804. [PMID: 17628492 DOI: 10.1002/jps.21021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The present study evaluated the effect of endotoxin-induced systemic inflammation on cardiac uptake and negative inotropic response to verapamil in isolated rat hearts. Rats received an i.p. dose of 4 mg/kg Escherichia coli lipopolysaccharide (LPS) or saline. After 5.5 h the outflow concentration-time curve and inotropic response data were measured following a 1.5 nmol dose of [(3)H]-verapamil (infused within 1 min) in Langendorff-perfused hearts and analyzed by pharmacokinetic/pharmacodynamic modeling, where the inotropic effects at individual time points were evaluated in relation to outflow concentrations at corresponding times. Endotoxemia decreased the rate of cardiac verapamil uptake and the maximal negative inotropic effect E(max) to 78% and 55%, respectively, of the values estimated in the control group (p < 0.01). The reduction in E(max) was correlated with the increase in body temperature. With verapamil as a model drug, the results give some information about potential effects of endotoxemia on the cardiac kinetics and dynamics of calcium antagonists.
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Affiliation(s)
- Pakawadee Sermsappasuk
- Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, 06097 Halle, Germany
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Trzeciak S, Cinel I, Phillip Dellinger R, Shapiro NI, Arnold RC, Parrillo JE, Hollenberg SM. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 2008; 15:399-413. [PMID: 18439194 DOI: 10.1111/j.1553-2712.2008.00109.x] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: 1) the central role of the microcirculation in the pathophysiology of sepsis; 2) new translational research techniques of in vivo video microscopy for assessment of microcirculatory flow in human subjects; 3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; 4) the potential role of novel agents to "rescue" the microcirculation in sepsis; 5) current challenges facing this emerging field of clinical investigation; and 6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide (NO) molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis). We also present the scientific rationale for clinical trials of exogenous NO administration to treat microcirculatory dysfunction and augment microcirculatory blood flow in early sepsis therapy.
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Affiliation(s)
- Stephen Trzeciak
- Department of Emergency Medicine, Division of Critical Care Medicine, University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, NJ, USA.
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Menzies-Gow NJ, Sepulveda MF, Bailey SR, Cunningham FM, Elliott J. Roles of thromboxane A2and 5-hydroxytryptamine in endotoxin-induced digital vasoconstriction in horses. Am J Vet Res 2008; 69:199-207. [DOI: 10.2460/ajvr.69.2.199] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Bateman RM, Tokunaga C, Kareco T, Dorscheid DR, Walley KR. Myocardial hypoxia-inducible HIF-1alpha, VEGF, and GLUT1 gene expression is associated with microvascular and ICAM-1 heterogeneity during endotoxemia. Am J Physiol Heart Circ Physiol 2007; 293:H448-56. [PMID: 17369472 DOI: 10.1152/ajpheart.00035.2007] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The systemic inflammatory response to infection is the leading cause of mortality in North American intensive-care units. Although much is known about inflammatory mediators, the relationships between microregional inflammation, microvascular heterogeneity, hypoxia, hypoxia-inducible gene expression, and myocardial dysfunction are unknown. Male Sprague-Dawley rats were injected intraperitoneally with LPS to test the hypothesis that sepsis-induced local inflammation and increased microvascular heterogeneity are spatially and temporally associated with hypoxia, hypoxia-inducible gene expression, and decreased left-ventricular contractility. Using a combination of three-dimensional microvascular imaging, tissue Po(2), and pressure-volume conductance measurements, we found that 5 h after LPS, minimum oxygen-diffusion distances increased (P < 0.05), whereas tissue oxygenation and contractility both decreased (P < 0.05) in the left ventricle. Real-time RT-PCR analysis revealed that the hypoxia-inducible genes hypoxia-inducible factor (HIF)-1alpha, VEGF, and glucose transporter (GLUT) 1 were all upregulated (P < 0.05) in the left ventricle. Tissue regions expressing ICAM-1, obtained by using laser-capture microdissection, had increased HIF-1alpha and GLUT1 (P < 0.05) gene expression. VEGF gene expression was more diffuse. In LPS rats, GLUT1 gene expression correlated (P < 0.05) with left-ventricular contractility. In 5-h hypoxic cardiomyocytes, we found strong transient HIF-1alpha, weak VEGF, and greater prolonged GLUT1 gene expression. By comparison, the HIF-1alpha-GLUT1 gene-induction pattern was reversed in the left ventricle of LPS rats. Together, these results show that LPS induces hypoxia in the left ventricle associated with increased microvascular heterogeneity and decreased contractility. HIF-1alpha and GLUT1 gene induction are related to a heterogeneous ICAM-1 expression and may be cardioprotective during the onset of septic injury.
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Affiliation(s)
- Ryon M Bateman
- University of British Columbia Critical Care Research Laboratories, Department of Medicine, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada
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Kane GC, Lam CF, O'Cochlain F, Hodgson DM, Reyes S, Liu XK, Miki T, Seino S, Katusic ZS, Terzic A. Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia. FASEB J 2006; 20:2271-80. [PMID: 17077304 DOI: 10.1096/fj.06-6349com] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 K(ATP) channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress-responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a K(ATP) channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.
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Affiliation(s)
- Garvan C Kane
- Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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Farand P, Hamel M, Lauzier F, Plante GE, Lesur O. Review article: Organ per fusion/permeabilityrelated effects of norepinephrine and vasopressin in sepsis. Can J Anaesth 2006; 53:934-46. [PMID: 16960272 DOI: 10.1007/bf03022837] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
PURPOSE One invariable hallmark of severe sepsis is generalized tissue "malperfusion" and hyperpermeability secondary to microcirculatory/capillary leakage. This review focuses on direct and/or indirect influences of norepinephrine, as a standard of care, and vasopressin, as an alternative vasoactive drug, on organ and tissue perfusion/permeability in severe sepsis. SOURCE English and French language articles and books published between 1966 and 2005 were identified through a computerized Medline search using the terms "sepsis, permeability, norepinephrine and vasopressin". Relevant publications were retrieved and scanned for additional sources. PRINCIPAL FINDINGS There are few randomized clinical trials comparing different vasopressors in sepsis; most available literature consists of clinical reports, animal experiments and occasional reviews. Based on the best current evidence from these sources, we describe the status of major organ perfusion/permeability in sepsis (i.e., the lung, the kidney, the heart, the intestine/gut) in the context of sepsis-induced organ dysfunction/failure. Potential and differential therapeutic effects of the vasopressors norepinephrine and arginine-vasopressin, in the setting of sepsis, are identified. CONCLUSIONS In the treatment of sepsis, arginine-vasopressin exhibits organ-specific heterogeneity in vascular responsiveness, compared to norepinephrine. While norepinephrine is a current standard of care in sepsis, arginine-vasopressin shows promise for the treatment of septic shock.
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Affiliation(s)
- Paul Farand
- Laboratoire de Physiologie Rénale et Vasculaire, Quebec, Canada
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Asfar P, Hauser B, Radermacher P, Matejovic M. Catecholamines and vasopressin during critical illness. Crit Care Clin 2006; 22:131-49, vii-viii. [PMID: 16399024 DOI: 10.1016/j.ccc.2005.08.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
In critical care medicine, catecholamines are most widely used to reverse circulatory dysfunction and thus to restore tissue perfusion. However, catecholamines not only influence systemic and regional hemodynamics, but also exert a variety of significant metabolic, endocrine, and immunologic effects. Arginine vasopressin is a vasomodulatory hormone with potency to restore vascular tone in vasodilatory hypotension. Although the evidence supporting the use of low doses of vasopressin or its analogs in vasodilatory shock is increasing, lack of data regarding mortality and morbidity prevent their implementation in critical care protocols.
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Affiliation(s)
- Pierre Asfar
- Département de Réanimation Médicale, Centre Hospitalier Universitaire, 4 rue Larry, 49993 Angers Cedex 9, France
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Abstract
Sepsis--a state of systemic bacterial infection--often leads to multiorgan failure and is associated with high mortality despite the recent advances achieved in intensive care treatment. Many of the ill effects of sepsis are attributed to an abnormally enhanced host inflammatory response that leads to neutrophil recruitment and activation involving selectins, a class of adhesion molecules, in the initial stages. Nitric oxide and its various isoforms have also been implicated in various vascular alterations and directly participate in the cellular toxicity in sepsis. This review briefly describes the role of selectins and nitric oxide in experimental and clinical sepsis as well as the therapeutic outcomes of blocking therapies.
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Affiliation(s)
- Abhijit Chandra
- Department of Surgery, King George Medical University--Lucknow, India
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Pevni D, Frolkis I, Shapira I, Schwartz D, Schwartz IF, Chernichovski T, Lev-Ran O, Sharony R, Uretzky G. Ischaemia or reperfusion: which is a main trigger for changes in nitric oxide mRNA synthases expression? Eur J Clin Invest 2005; 35:546-50. [PMID: 16128860 DOI: 10.1111/j.1365-2362.2005.01553.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To investigate alterations in endothelial nitric oxide synthase and inducible nitric oxide synthase mRNA expressions and nitric oxide release in the myocardium during ischaemia/reperfusion and determine whether these changes are ischaemic and/or reperfusion dependent. MATERIALS AND METHODS Isolated rat hearts were perfused by a modified Langendorff system. Following 1 h of global cardioplegic ischaemia, left ventricle haemodynamic parameters were recorded at baseline and during 30 min of reperfusion. Levels of endothelial, inducible nitric oxide synthases mRNA expression and nitric oxide release were measured at baseline, after ischaemia and at 30 min of reperfusion. RESULTS Global cardioplegic ischaemia caused a significant depression of left ventricular function and a decrease of coronary flow. Postischaemic intensities of the endothelial nitric oxide synthase mRNA bands were significantly lower than at baseline (P < 0.01). There were no significant differences in endothelial nitric oxide synthase mRNA band intensities immediately after ischaemia compared to the end of reperfusion, nor between the intensities of inducible nitric oxide synthase mRNA bands at baseline, at end of ischaemia and at end of reperfusion. Nitric oxide in the myocardial effluent was below detectable levels at all measured points. CONCLUSION Ischaemic injury causes down-regulation of endothelial nitric oxide synthase mRNA expression, which is then associated with reduction of coronary flow during reperfusion, representing one possible mechanism of ischaemia/reperfusion injury. We did not find expected elevations of inducible nitric oxide synthase mRNA expression during ischaemia or reperfusion and we suggest that ischaemia/reperfusion injury is not associated with nitric oxide overproduction.
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Affiliation(s)
- D Pevni
- Department of Cardiothoracic Surgery, Tel Aviv University, Tel Aviv, Israel
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Abstract
Regional tissue distress caused by microcirculatory dysfunction and mitochondrial depression underlies the condition in sepsis and shock where, despite correction of systemic oxygen delivery variables, regional hypoxia and oxygen extraction deficit persist. We have termed this condition microcirculatory and mitochondrial distress syndrome (MMDS). Orthogonal polarization spectral imaging allowed the first clinical observation of the microcirculation in human internal organs, and has identified the pivotal role of microcirculatory abnormalities in defining the severity of sepsis, a condition not revealed by systemic hemodynamic or oxygen-derived variables. Recently, sublingual sidestream dark-field (SDF) imaging has been introduced, allowing observation of the microcirculation in even greater detail. Microcirculatory recruitment is needed to ensure adequate microcirculatory perfusion and the oxygenation of tissue cells that follows. In sepsis, where inflammation-induced autoregulatory dysfunction persists and oxygen need is not matched by supply, the microcirculation can be recruited by reducing pathological shunting, promoting microcirculatory perfusion, supporting pump function, and controlling hemorheology and coagulation. Resuscitation following MMDS must include focused recruitment of hypoxic-shunted microcirculatory units and/or resuscitation of the mitochondria. A combination of agents is required for successful rescue of the microcirculation. Single compounds such as activated protein C, which acts on multiple pathways, can be expected to be beneficial in rescuing the microcirculation in sepsis.
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Affiliation(s)
- Can Ince
- Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Siegemund M, van Bommel J, Schwarte LA, Studer W, Girard T, Marsch S, Radermacher P, Ince C. Inducible nitric oxide synthase inhibition improves intestinal microcirculatory oxygenation and CO2 balance during endotoxemia in pigs. Intensive Care Med 2005; 31:985-92. [PMID: 15959764 DOI: 10.1007/s00134-005-2664-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2004] [Accepted: 05/04/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVE We examined whether selective inhibition of inducible nitric oxide synthase (iNOS) promotes intestinal microvascular oxygenation (microPO2) and CO2 off-load after endotoxic shock. DESIGN AND SETTING Prospective, controlled experimental study in a university animal research laboratory. SUBJECTS 13 domestic pigs. INTERVENTIONS After baseline measurements shock was induced by 1 microg kg-1 h-1 endotoxin until mean arterial pressure fell below 60 mmHg. After 30 min in shock the animals were resuscitated with either fluid alone (control, n=6) or fluid and the iNOS inhibitor N-[3-(aminomethyl)benzyl]acetamidine hydrochloride (1400W, n=7). As final experimental intervention all animals received the nonselective NOS inhibitor L-NAME. MEASUREMENTS AND RESULTS Systemic and regional hemodynamic and oxygenation parameters were measured at baseline, during endotoxemia and shock, hourly for 3 h of 1400W therapy, and 30 min after the final L-NAME administration. microPO2 was assessed by the Pd-porphyrin phosphorescence technique, and the arterial to intestinal PCO2 gap was determined by air tonometry. Endotoxemia and shock resulted in a decrease in ileal mucosal and serosal microPO2 and a rise in PCO2 gap. The combination of 1400W and fluid resuscitation, but not fluid alone, normalized both the serosal microPO2 and the intestinal PCO2 gap. Administration of L-NAME decreased cardiac output and oxygen delivery and intestinal microPO2 and blood flow in both groups. CONCLUSIONS Partial blockade of NO production by 1400W increased serosal microvascular oxygenation and decreased the intestinal CO2 gap. This findings are consistent with the idea that 1400W corrects pathological flow distribution and regional dysoxia within the intestinal wall following endotoxic shock.
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Affiliation(s)
- Martin Siegemund
- Department of Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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Faber P, Ronald A, Millar BW. Methylthioninium chloride: pharmacology and clinical applications with special emphasis on nitric oxide mediated vasodilatory shock during cardiopulmonary bypass. Anaesthesia 2005; 60:575-87. [PMID: 15918829 DOI: 10.1111/j.1365-2044.2005.04185.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Vasodilatory shock after cardiopulmonary bypass is a common complication requiring treatment with high doses of inotropes and prolonged stays in the intensive care unit. The vasodilatory shock is initiated by an inflammatory response to the extracorporeal circuit. The inflammatory response results in endothelial synthesis and release of nitric oxide resembling the clinical features observed in vasodilatory shock caused by septicaemia. During vasodilatory shock, the inhibition of nitric oxide synthase and the nitric oxide/cyclic guanylyl monophosphate pathway is an attractive adjunct to therapy with traditional inotropes. Methylthioninium chloride inhibits nitric oxide/cyclic guanylyl monophosphate mediated vasodilation and can successfully be used as a supplement in the treatment of vasodilatory shock associated with cardiopulmonary bypass. The application of methylthioninium chloride in septicaemia has not produced comparable positive clinical results.
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Affiliation(s)
- P Faber
- Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK.
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Lee CC, Lin NT, Hsu YH, Chen HI. Inducible Nitric Oxide Synthase Inhibition Potentiates Multiple Organ Dysfunction Induced by Endotoxin in Conscious Rats. J Cardiovasc Pharmacol 2005; 45:396-403. [PMID: 15821434 DOI: 10.1097/01.fjc.0000157438.72483.ae] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
This study was designed to investigate the effects of inducible nitric oxide synthase (iNOS) inhibition with S-methylisothiourea (SMT) and L-N-(1-iminoethyl)-lysine (L-Nil) on the endotoxemia induced by intravenous lipopolysaccharide (LPS, 10 mg/kg) in conscious rats. Arterial pressure (AP), heart rate (HR), WBC, platelets, plasma nitrite/nitrate, tumor necrosis factor alpha (TNF alpha), and biochemical factors were measured for 24 hours after LPS with or without iNOS inhibitors. RT-PCR was employed to determine the iNOS and endothelial NOS (eNOS) mRNA. Pathologic examinations of the liver and heart were performed. SMT and L-Nil improved the systemic hypotension and increased the HR after LPS. These agents attenuated the LPS-induced leukocytopenia and thrombocytopenia and the increase in nitrite/nitrate. However, iNOS inhibition aggravated the LPS-induced changes in TNF alpha, all biochemical factors, and the hepatic and cardiac tissue damage. The iNOS mRNA, but not the eNOS, was reduced. Our results in conscious rats indicate that iNOS inhibition enhances the organ dysfunction and tissue damage in sepsis. The discrepancy may be attributed to the method for evaluating the sepsis and the effects of anesthesia. Further investigation is required to ensure the effects of iNOS inhibition on sepsis before iNOS inhibitors can be applied in clinical cases with sepsis.
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Affiliation(s)
- Chia-Chi Lee
- Institute of Medical Science, Tzu Chi University, Hualien, Taiwan
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Xavier-Vidal R. Oxytalan elastic and collagen fibers during the repair process in experimental nitric oxide inhibition. Clinics (Sao Paulo) 2005; 60:85-92. [PMID: 15880243 DOI: 10.1590/s1807-59322005000200003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
PURPOSE To evaluate the repair process in rats with experimentally induced arterial hypertension. This study aimed to evaluate lesions in the ventricular myocardium and the repair process during experimental hypertension induced by systemic blockage of nitric oxide using N-omega-nitro-L-arginine methyl ester hydrochloride (L-NAME). Nitric oxide is an endothelial vasorelaxing factor and is necessary for the maintenance of normal arterial pressure, and L-NAME is an analog and antagonist of L-arginine, the substrate of the nitric oxide synthase. MATERIALS AND METHODS We used 26 normotensive young male Wistar rats belonging to several litters. Animals were treated with oral administration of L-NAME dissolved in water (75 mg/100 mL) for 43 days. Hearts were weighed and processed by routine methods. Special stains utilized were Gomori's trichrome (aniline blue), picrosirius red polarization to identify fibrillar collagen, alcian blue technique (pH 0.5 and pH 2.5) to identify glycosaminoglycans, periodic acid-Schiff technique (with and without amylases) to identify proteoglycans, and Weigert's resorcinol fuchsin solution (with and without oxone) to identify elastic fibers. RESULTS The results showed significant elevation of the arterial pressure (P <0.01) and significant increase of cardiac weight (P <.0001) in the L-NAME (hypertensive) treated group, as compared to an untreated control group. The histological analysis demonstrated wide infarcted myocardial areas in animals with nitric oxide blockade; several vascular changes such as thickening of the muscular tunica with fibrosis; thickening in the wall of small arteries and arterioles; and fibrinoid necrosis in the wall to nearly complete luminal obliteration. Reparative fibrosis involved mainly oxytalan elastic and collagen fibers. CONCLUSION Oxytalan elastic and collagen fibers are of great importance for the postinfarct repair process occurring during experimental nitric oxide inhibition.
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Affiliation(s)
- Ricardo Xavier-Vidal
- Biological and Ambient Science Institute, Santa Ursula University, Rio de Janeiro, RJ, Brazil.
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Asfar P, Hauser B, Iványi Z, Ehrmann U, Kick J, Albicini M, Vogt J, Wachter U, Brückner UB, Radermacher P, Bracht H. Low-dose terlipressin during long-term hyperdynamic porcine endotoxemia: effects on hepatosplanchnic perfusion, oxygen exchange, and metabolism. Crit Care Med 2005; 33:373-80. [PMID: 15699842 DOI: 10.1097/01.ccm.0000152253.45901.fb] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To investigate whether the vasopressin analog terlipressin might induce hepatosplanchnic ischemia during long-term, hyperdynamic, volume-resuscitated porcine endotoxemia. DESIGN Prospective, randomized, controlled experimental study with repeated measures. SETTING Investigational animal laboratory. SUBJECTS Eighteen pigs were divided into two groups receiving either endotoxin alone (control group, n = 10) or endotoxin and terlipressin (n = 8). INTERVENTIONS Pigs were anesthetized, mechanically ventilated, and instrumented and received a continuous intravenous infusion of Escherichia coli endotoxin. Animals were resuscitated with hydroxyethyl starch targeted to maintain mean arterial pressure >60 mm Hg. Twelve hours after the start of the endotoxin infusion, terlipressin (5-15 microg.kg.hr titrated to maintain mean arterial pressure at preendotoxin levels) or its vehicle was administered for 12 hrs. MEASUREMENTS AND MAIN RESULTS Terlipressin increased mean arterial pressure and systemic vascular resistances, which was affiliated with a decrease in cardiac output and global oxygen consumption. Terlipressin restored the hepatic artery buffer response, which led to an increase in hepatic artery flow, ultimately resulting in well-maintained liver oxygen delivery, oxygen uptake, and all other variables of regional metabolism and organ function. Terlipressin markedly attenuated the hepatosplanchnic venous acidosis but was associated with pronounced hyperlactatemia. CONCLUSIONS During long-term hyperdynamic porcine endotoxemia, the well-known vasoconstrictor properties of terlipressin blunted the progressive decrease in mean arterial pressure without any detrimental effect on hepatosplanchnic perfusion, oxygen exchange, and metabolism. The marked terlipressin-induced hyperlactatemia did not originate from the hepatosplanchnic organs but from extrasplanchnic tissues, possibly muscle and skin.
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Affiliation(s)
- Pierre Asfar
- Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany
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Siroen MPC, van Leeuwen PAM, Nijveldt RJ, Teerlink T, Wouters PJ, Van den Berghe G. Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: A possible explanation of reduced morbidity and mortality?*. Crit Care Med 2005; 33:504-10. [PMID: 15753739 DOI: 10.1097/01.ccm.0000155784.59297.50] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Asymmetric dimethylarginine, which inhibits production of nitric oxide, has been shown to be a strong and independent predictor of mortality in critically ill patients with clinical evidence of organ dysfunction. Interestingly, intensive insulin therapy in critically ill patients improved morbidity and mortality, but the exact mechanisms by which these beneficial effects are brought about remain unknown. Therefore, we aimed to investigate whether modulation of asymmetric dimethylarginine concentrations by intensive insulin therapy is involved in these effects. DESIGN A prospective, randomized, controlled trial. SETTING A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. PATIENTS From a study of 1,548 critically ill patients who were randomized to receive either conventional or intensive insulin therapy, we included 79 patients who were admitted to the intensive care unit after complicated pulmonary and esophageal surgery and required prolonged (>/=7 days) intensive care. INTERVENTIONS Determination of asymmetric dimethylarginine concentrations. MEASUREMENTS AND MAIN RESULTS Asymmetric dimethylarginine concentrations were determined with high-performance liquid chromatography on the day of admission, on day 2, on day 7, and on the last day at the intensive care unit. Although the asymmetric dimethylarginine levels did not change between day 0 and day 2 in patients receiving intensive insulin treatment, there was a significant increase during this period in the conventionally treated patients (p = .043). Interestingly, the mean daily insulin dose was inversely associated with the asymmetric dimethylarginine concentration on the last day (r = -.23, p = .042), and the asymmetric dimethylarginine concentration on the last day at the intensive care unit was significantly lower in the intensive insulin treatment group (p = .048). Furthermore, asymmetric dimethylarginine was positively associated with duration of intensive care unit stay, duration of ventilatory support, duration of inotropic and vasopressor treatment, number of red cell transfusions, duration of antibiotic treatment, presence of critical illness polyneuropathy, mean Acute Physiology and Chronic Health Evaluation II score, and cumulative Therapeutic Intervention Scoring System-28 score. In addition, asymmetric dimethylarginine levels in patients who died were significantly higher compared with survivors, and changes in the course of asymmetric dimethylarginine plasma concentrations were predictive for adverse intensive care unit outcome. CONCLUSIONS Modulation of asymmetric dimethylarginine concentration by insulin at least partly explains the beneficial effects found in critically ill patients receiving intensive insulin therapy.
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Affiliation(s)
- Michiel P C Siroen
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
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Eerbeek O, Mik EG, Zuurbier CJ, van 't Loo M, Donkersloot C, Ince C. Ratiometric intracellular calcium imaging in the isolated beating rat heart using indo-1 fluorescence. J Appl Physiol (1985) 2004; 97:2042-50. [PMID: 15208283 DOI: 10.1152/japplphysiol.01125.2003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Abnormalities in intracellular calcium (Cai2+) handling have been implicated as the underlying mechanism in a large number of pathologies in the heart. Study into the relation between Cai2+behavior and performance of the whole heart function could provide detailed information into the cellular basis of heart function. In this study we describe an optical ratio imaging setup and an analysis method for the beat-to-beat Cai2+videofluorescence images of an indo-1 loaded, isolated Tyrode-perfused beating rat heart. The signal-to-noise ratio and the spatiotemporal resolution (with an optimum of 1 ms and 0.6 mm, respectively) made it possible to register different temporal Cai2+transients together with left ventricle pressure changes. The Cai2+transients showed that Cai2+activation propagates horizontally from left to right during sinus rhythm or from the stimulus site during direct left ventricle stimulation. The indo-1 ratiometric video technique developed allows the imaging of ratio changes of Cai2+with a high temporal (1 ms) and spatial (0.6 mm) resolution in the isolated Tyrode-perfused beating rat heart.
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Affiliation(s)
- Otto Eerbeek
- Dept. of Physiology, Academic Medical Center, Univ. of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
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Bakker J, Grover R, McLuckie A, Holzapfel L, Andersson J, Lodato R, Watson D, Grossman S, Donaldson J, Takala J. Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med 2004; 32:1-12. [PMID: 14707554 DOI: 10.1097/01.ccm.0000105118.66983.19] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure > or =70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DESIGN Multicentered, randomized, placebo-controlled, safety and efficacy study. SETTING Forty-eight intensive care units in Europe, North America, and Australia. PATIENTS A total of 312 patients with septic shock diagnosed within 24 hr before randomization. INTERVENTIONS Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). MEASUREMENTS AND MAIN RESULTS Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p =.004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. CONCLUSIONS In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.
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Affiliation(s)
- Jan Bakker
- Department of Intensive Care, Gelre Lukas Hospital, Apeldoorn, The Netherlands
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Paz Y, Frolkis I, Pevni D, Shapira I, Yuhas Y, Iaina A, Wollman Y, Chernichovski T, Nesher N, Locker C, Mohr R, Uretzky G. Effect of tumor necrosis factor-alpha on endothelial and inducible nitric oxide synthase messenger ribonucleic acid expression and nitric oxide synthesis in ischemic and nonischemic isolated rat heart. J Am Coll Cardiol 2003; 42:1299-305. [PMID: 14522499 DOI: 10.1016/s0735-1097(03)00992-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVES The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-alpha) that was synthesized during ischemia and exogenous TNF-alpha on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart. BACKGROUND Tumor necrosis factor-alpha is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-alpha-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-alpha-induced myocardial dysfunction is highly controversial. METHODS Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-alpha on the expression of eNOS mRNA and iNOS mRNA and on NO production. RESULTS After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 +/- 0.08 to 0.68 +/- 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-alpha had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 +/- 0.04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels. CONCLUSIONS We believe this is the first study to directly show that TNF-alpha does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.
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Affiliation(s)
- Yosef Paz
- Department of Thoracic and Cardiovascular Surgery, Tel-Aviv University, Tel-Aviv, Israel
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Sibelius U, Grandel U, Buerke M, Kiss L, Klingenberger P, Heep M, Bournelis E, Seeger W, Grimminger F. Leukotriene-mediated coronary vasoconstriction and loss of myocardial contractility evoked by low doses of Escherichia coli hemolysin in perfused rat hearts. Crit Care Med 2003; 31:683-8. [PMID: 12626969 DOI: 10.1097/01.ccm.0000050072.69509.06] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE hemolysin has been implicated as an important pathogenic factor in extraintestinal infections including sepsis. We investigated the effects of coronary administration of hemolysin on cardiac function in isolated rat hearts perfused at constant flow. DESIGN Prospective, experimental study. SETTING Research laboratory at a university hospital. SUBJECTS Isolated hearts from male Wistar rats. INTERVENTIONS Isolated hearts were perfused with purified hemolysin for 60 min. MEASUREMENTS AND MAIN RESULTS Low concentrations of the toxin in the perfusate (0.1-0.2 hemolytic units/mL) caused a dose-dependent coronary vasoconstriction with a marked increase in coronary perfusion pressure, which was paralleled by a decrease in left ventricular developed pressure (and the maximum rate of left ventricular pressure increase). Moreover, 0.2 hemolytic units/mL hemolysin evoked ventricular fibrillation within 10 mins of toxin application. These events were accompanied by the liberation of leukotrienes (LTC4, LTD4, LTE4, and LTB4), thromboxane A2, prostaglandin I2, and the cell necrosis markers lactate dehydrogenase and creatine kinase into the recirculating perfusate. The lipoxygenase inhibitor MK-886 fully blocked the toxin-induced coronary vasoconstrictor response and the loss of myocardial contractility and reduced the release of lactate dehydrogenase and creatine kinase. In contrast to this, the cyclooxygenase inhibitor indomethacin was entirely ineffective. In addition, hemolysin elicited an increase in heart weight and left ventricular end-diastolic pressure, the latter again being suppressed by MK-886. CONCLUSIONS Low doses of hemolysin cause strong coronary vasoconstriction, linked with loss of myocardial performance, release of cell injury enzymes, and electrical instability, with all events being largely attributable to toxin-elicited leukotriene generation in the coronary vasculature. Bacterial exotoxins such as hemolysin thus may be implicated in the cardiac abnormalities encountered in septic shock.
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Affiliation(s)
- Ulf Sibelius
- Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany
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Asfar P, Pierrot M, Veal N, Moal F, Oberti F, Croquet V, Douay O, Gallois Y, Saumet JL, Alquier P, Calès P. Low-dose terlipressin improves systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats. Crit Care Med 2003; 31:215-20. [PMID: 12545018 DOI: 10.1097/00003246-200301000-00033] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Vasopressin has been used to treat arterial hypotension associated with hyperdynamic vasoplegic states, but detrimental effects on splanchnic circulation have been reported. We tested the effects of a low-dose vasopressin analogue, terlipressin (6 microg/kg), on systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats (lipopolysaccharide, 30 mg/kg in 1 hr). DESIGN Prospective, randomized, controlled experimental study with repeated measures. SETTING Investigational animal laboratory. SUBJECTS A total of 77 rats were divided into five groups: group C, control (17 rats); group E, LPS (18 rats); group EF, LPS plus fluid challenge (18 rats); group EFT, LPS plus fluid challenge plus terlipressin (18 rats); and group ET, LPS plus terlipressin (seven rats). INTERVENTIONS Rats were anesthetized, mechanically ventilated, and instrumented to measure heart rate, mean arterial pressure, and abdominal aortic and mesenteric vein indexed blood flows; ileal microcirculation was assessed by laser Doppler. After LPS infusion, rats experienced an endotoxic shock and were resuscitated after the allocation group. The fluid challenge was targeted to maintain mean arterial pressure of >90 mm Hg and aortic blood flow at baseline values. MEASUREMENTS AND MAIN RESULTS Terlipressin significantly (p <.05) increased mean arterial pressure without decreasing indexed aortic blood flow and heart rate in the fluid-challenged endotoxic rats (EFT) compared with EF rats and had detrimental effects in hypodynamic endotoxic rats (ET). Fluid challenge significantly (p <.05) increased mesenteric vein blood flow in both the EF and EFT groups, and terlipressin had no detrimental effect on mesenteric blood flow. Terlipressin significantly (p <.05) increased ileal microcirculation in fluid-challenged endotoxic rats (EF and EFT) but not in hypodynamic endotoxic rats (E and ET). CONCLUSION Low-dose terlipressin in fluid-challenged endotoxic rats improved systemic and splanchnic hemodynamics and improved the ileal microcirculation.
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Bateman RM, Sharpe MD, Ellis CG. Bench-to-bedside review: microvascular dysfunction in sepsis--hemodynamics, oxygen transport, and nitric oxide. Crit Care 2003; 7:359-73. [PMID: 12974969 PMCID: PMC270719 DOI: 10.1186/cc2353] [Citation(s) in RCA: 193] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The microcirculation is a complex and integrated system that supplies and distributes oxygen throughout the tissues. The red blood cell (RBC) facilitates convective oxygen transport via co-operative binding with hemoglobin. In the microcirculation oxygen diffuses from the RBC into neighboring tissues, where it is consumed by mitochondria. Evidence suggests that the RBC acts as deliverer of oxygen and 'sensor' of local oxygen gradients. Within vascular beds RBCs are distributed actively by arteriolar tone and passively by rheologic factors, including vessel geometry and RBC deformability. Microvascular oxygen transport is determined by microvascular geometry, hemodynamics, and RBC hemoglobin oxygen saturation. Sepsis causes abnormal microvascular oxygen transport as significant numbers of capillaries stop flowing and the microcirculation fails to compensate for decreased functional capillary density. The resulting maldistribution of RBC flow results in a mismatch of oxygen delivery with oxygen demand that affects both critical oxygen delivery and oxygen extraction ratio. Nitric oxide (NO) maintains microvascular homeostasis by regulating arteriolar tone, RBC deformability, leukocyte and platelet adhesion to endothelial cells, and blood volume. NO also regulates mitochondrial respiration. During sepsis, NO over-production mediates systemic hypotension and microvascular reactivity, and is seemingly protective of microvascular blood flow.
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Affiliation(s)
- Ryon M Bateman
- Vascular Biology Program, Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada.
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Walley KR, McDonald TE, Wang Y, Dai S, Russell JA. Albumin resuscitation increases cardiomyocyte contractility and decreases nitric oxide synthase II expression in rat endotoxemia. Crit Care Med 2003; 31:187-94. [PMID: 12545014 DOI: 10.1097/00003246-200301000-00029] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Hypotension and hypoperfusion during septic shock may contribute to tissue hypoxia and the intramyocardial inflammatory response that results in myocardial dysfunction. Therefore, we hypothesized that crystalloid or colloid resuscitation may alter myocardial dysfunction. DESIGN Randomized, controlled, prospective animal study. SETTING University animal laboratory. SUBJECTS Sprague-Dawley rats (250-300 g, n = 6/group). INTERVENTIONS Rats received an intraperitoneal injection of 10 mg/kg lipopolysaccharide or control. One hour later, rats were randomized to intravenous resuscitation and received either 30 mL/kg normal saline, 10 mL/kg 10% pentastarch, 10 mL/kg 5% rat albumin, or no volume. MEASUREMENTS AND MAIN RESULTS We measured fractional shortening of cardiomyocytes isolated 5 hrs after lipopolysaccharide or control injection. In separate identical experiments, we measured myocardial interleukin-6, macrophage inhibitory protein-2, and nitric oxide synthase II protein and messenger RNA expression. Control fractional shortening of 24.1 +/- 2.2% was decreased by lipopolysaccharide to 18.8 +/- 1.2% (p <.001). Volume resuscitation after lipopolysaccharide significantly improved fractional shortening (p <.001). In particular, albumin resuscitation increased fractional shortening to 23.5 +/- 0.9%, which was more than either saline (fractional shortening 20.1 +/- 1.7%,p <.01) or pentastarch (fractional shortening 21.4 +/- 0.9%,p <.01). Myocardial macrophage inhibitory protein-2 protein and interleukin-6 and macrophage inhibitory protein-2 messenger RNA expression and neutrophil content were elevated following lipopolysaccharide (p <.05) but were not altered by volume resuscitation. Myocardial nitric oxide synthase II protein and messenger RNA expression increased following lipopolysaccharide (p <.01) and decreased with albumin resuscitation. CONCLUSIONS We conclude that following lipopolysaccharide injection, volume resuscitation improves cardiomyocyte fractional shortening. Albumin resuscitation is particularly beneficial in preventing reduced cardiomyocyte contractility, and this benefit may be related to an albumin-induced reduction in nitric oxide synthase II protein and messenger RNA expression following endotoxin injection.
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Affiliation(s)
- Keith R Walley
- University of British Columbia McDonald Research Laboratories/iCAPTURE Center, Vancouver, Canada.
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Fitzal F, Redl H, Strohmaier W, Werner ER, Bahrami S. A 4-amino analogue of tetrahydrobiopterin attenuates endotoxin-induced hemodynamic alterations and organ injury in rats. Shock 2002; 18:158-62. [PMID: 12166780 DOI: 10.1097/00024382-200208000-00012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Most recently we have shown that 4-aminotetrahydrobiopterin (4-ABH4), an analogue of tetrahydrobiopterin (cofactor of NO synthase), even administered 2 h after endotoxin challenge, improves survival rate in rats. The following experiment was performed to examine the effects of 4-ABH4 with respect to endotoxin-induced hemodynamic alterations and organ failure. At 2 h after endotoxic challenge (10 mg kg(-1) body weight) animals received 4-ABH4 at a dose of 1, 10, or 100 mg kg(-1) body weight. The controls were treated similarly but received saline at the same volume. Eight hours after endotoxin challenge cardiac index and stroke volume were significantly increased in animals treated with 10 mg 4-ABH4 compared to controls (0.23 +/- 0.06 vs. 0.16 +/- 0.04 mL min(-1) kg(-1) and 0.29 +/- 0.05 vs. 0.22 +/- 0.03 mL beat(-1)) while mean arterial pressure and peripheral vascular resistance index did not significantly differ among the groups. Plasma alanine aminotransferase (ALT) and creatinine levels were significantly increased in endotoxin controls compared with laboratory controls (ALT: 1643 +/- 1436 vs. 74 +/- 17 U L(-1); Creatinine: 91 +/- 29 vs. 42 +/- 3 micromol L(-1)) which was attenuated in animals treated with 10 mg kg(-1) 4-ABH4 (ALT: 417 +/- 318 U L(-1); Creatinine: 78 +/- 26 micromol L(-1)). Moreover, endotoxin-induced lung edema and intestinal necrosis were significantly reduced by 4-ABH4. Our study provides information that tetrahydrobiopterin analogue, 4-ABH4, improves LPS induced hemodynamic conditions and organ injury. This may, at least in part, account for the previously observed protection of rats by 4-ABH4 against endotoxin-induced mortality in the same endotoxic shock model.
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Affiliation(s)
- Florian Fitzal
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
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Vona-Davis L, Wearden P, Hill J, Hill R. Cardiac response to nitric oxide synthase inhibition using aminoguanidine in a rat model of endotoxemia. Shock 2002; 17:404-10. [PMID: 12022762 DOI: 10.1097/00024382-200205000-00011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This study evaluates the effect of aminoguanidine, a preferential inhibitor of inducible nitric oxide synthase (iNOS), on the prevention of cardiac depression in acute endotoxemia. Cardiac performance was evaluated after 4 h of exposure to endotoxin. Rats (n = 5) were selected randomly to receive, by intraperitoneal injection, one of four treatments: saline, LPS (lipopolysaccharide, E. coli, 4 mg/kg, AG (aminoguanidine 100 mg/kg), and LPS + AG at various times. AG and saline treatments were administered 30 min before LPS and at 1 and 3 h after LPS injection. Hearts were perfused using the Langendorff isolated perfusion system and a balloon-tipped catheter was placed into the left ventricle to measure left ventricular developed pressure (LVDP). Myocyte contractile function was assessed with electrical field stimulation and video microscopy. Tissue was immunostained for the expression of iNOS and for nitrotyrosine, a byproduct of protein nitration by peroxynitrite. Perfused hearts from LPS-treated rats exhibited a 57% decrease (P < 0.05) in LVDP compared to saline-treated animals. No improvement in ventricular function was observed with the administration of AG. Similarly, cardiac myocytes prepared from LPS-treated animals demonstrated a significant (P < 0.05) reduction in percent and velocity of shortening and this effect was unaltered with the same dose of AG. AG administration significantly reduced serum nitrite/nitrate levels (P < 0.05) in endotoxemic rats to control levels. Localized expression of iNOS in the myocardium was lessened with AG treatment and was not associated with peroxynitrite formation in this model of endotoxemia. The results indicate that AG given in vivo before and after endotoxin (at a concentration sufficient to decrease NO production) did not reduce cardiac depression. We conclude that selective inhibition of iNOS and the reduction of NO production do not prevent cardiac dysfunction at an early stage in an acute model of endotoxemia.
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Affiliation(s)
- Linda Vona-Davis
- Department of Surgery, West Virginia University, C Byrd Health Sciences Center, Morgantown 26506-9238, USA
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Yang F, Comtois AS, Fang L, Hartman NG, Blaise G. Nitric oxide-derived nitrate anion contributes to endotoxic shock and multiple organ injury/dysfunction. Crit Care Med 2002; 30:650-7. [PMID: 11990929 DOI: 10.1097/00003246-200203000-00026] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Because nitrate represents the major end-product of nitric oxide in vivo and can affect enzyme activity, cell electrophysiological functions, and cell membrane integrity, we hypothesized that overaccumulated nitric oxide-derived nitrate anion in tissues or organs in vivo may contribute to endotoxic shock and multiple organ injury/dysfunction during endotoxemia. DESIGN Prospective, experimental animal study. SETTING Laboratory at a university hospital. SUBJECTS Sprague-Dawley rats. INTERVENTIONS Rats were injected intraperitoneally with 5, 10, or 20 mg/kg lipopolysaccharide or saline and were studied in groups at 0, 6, 12, and 24 hrs. MEASUREMENTS AND MAIN RESULTS Significant differences were seen between nitrate concentrations in the heart, lung, kidney, liver, brain, aorta, diaphragm, spleen, thymus, testis or ovary, hind limb muscle, intestine, adipose tissue, bone, bladder, urine and plasma, which imply a nitrate gradient between intracellular and extracellular compartments. Lipopolysaccharide significantly increased nitrate concentration at 12 hrs in most tissues and organs, except in the brain, adipose tissue, and muscle. It increased more in plasma than in tissues. The lipopolysaccharide dose-dependent nitrate concentration was observed only in the aorta and lungs. The nitrate concentration change was paralleled by the systemic inflammatory response syndrome, as indicated by alterations of myeloperoxidase activity and by impaired histologic and cellular membrane integrity in tissues and organs. Mean arterial pressure was negatively correlated with nitrate concentration modifications in the aorta during 24 hrs of endotoxemia. CONCLUSIONS These results collectively indicate that overaccumulated nitric oxide-derived nitrate anion in tissues or organs in vivo contributes to endotoxic shock and multiple organ injury/dysfunction during endotoxemia.
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Affiliation(s)
- Fan Yang
- Laboratory of Anesthesia, Centre hospitalier de l'Université de Montréal-Hôpital Notre-Dame and Université de Montréal, Québec, Canada.
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The Rationale for Vasodilator Therapy in Sepsis. Intensive Care Med 2002. [DOI: 10.1007/978-1-4757-5551-0_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Massion PB, Moniotte S, Balligand JL. Nitric oxide: does it play a role in the heart of the critically ill? Curr Opin Crit Care 2001; 7:323-36. [PMID: 11805529 DOI: 10.1097/00075198-200110000-00003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Nitric oxide regulates many aspects of myocardial function, not only in the normal heart but also in ischemic and nonischemic heart failure, septic cardiomyopathy, cardiac allograft rejection, and myocarditis. Accumulating evidence implicates the endogenous production of nitric oxide in the regulation of myocardial contractility, distensibility, heart rate, coronary vasodilation, myocardial oxygen consumption, mitochondrial respiration, and apoptosis. The effects of nitric oxide promote left ventricular mechanical efficiency, ie, appropriate matching between cardiac work and myocardial oxygen consumption. Most of these beneficial effects are attributed to the low physiologic concentrations generated by the constitutive endothelial or neuronal nitric oxide synthase. By contrast, inducible nitric oxide synthase generates larger concentrations of nitric oxide over longer periods of time, leading to mostly detrimental effects. In addition, the recently identified beta3-adrenoceptor mediates a negative inotropic effect through coupling to endothelial nitric oxide synthase and is overexpressed in heart failure. An imbalance between beta 1 and beta2-adrenoceptor and beta3-adrenoceptor, with a prevailing influence of beta3-adrenoceptor, may play a causal role in the pathogenesis of cardiac diseases such as terminal heart failure. Likewise, changes in the expression of endothelial nitric oxide synthase or inducible nitric oxide synthase within the myocardium may alter the delicate balance between the effects of nitric oxide produced by either of these isoforms. New treatments such as selective inducible nitric oxide synthase blockade, endothelial nitric oxide synthase promoting therapies, and selective beta3-adrenoceptor modulators may offer promising new therapeutic approaches to optimize the care of critically ill patients according to their stage and specific underlying disease process.
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Affiliation(s)
- P B Massion
- Department of Internal Medicine, Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Brussels, Belgium
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