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Paz IA, Silva Filho PM, Leitão Junior AS, Pessoa TO, Santiago RO, Oliveira NOD, Longhinotti E, Sousa EHS, Lopes LGF, Santos CF, Fonteles MC, Nascimento NRF. Pharmacological evaluation of a new nanoformulation in the erectile tissue of rabbits and humans. Eur J Pharmacol 2024; 985:177071. [PMID: 39447860 DOI: 10.1016/j.ejphar.2024.177071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/20/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
The failure of achieving a penile erection for satisfactory sexual intercourse is known as erectile dysfunction (ED). The primary mediator for penile erection is nitric oxide (NO). ED is often associated with endothelial/nitrergic dysfunction characterized by a reduction of the bioavailability of NO. Phosphodiesterase-5 inhibitors (PDE-5Is) clinical efficacy in the treatment of ED depends on the integrity of the NO-sGC-PKG pathway. In the present study, we probed the effect of sodium nitroprusside incorporated into mesoporous silica nanoparticles (MPSi-NP), which traps cyanide and slowly releases NO. MPSi-NP induced a maximal relaxation of 92.8 ± 5.2% in rabbit corpora cavernosa (RbCC), blunted by a soluble guanylate cyclase (sGC) inhibitor and blockers of calcium-dependent potassium channels. MPSi-NP abolished spontaneous contractions of human corpora cavernosa (HCC) strips. In addition, MPSi-NP induced maximal relaxation of phenylephrine precontracted HCC by 118.6 ± 3.6%, and in comparison, tadalafil induced a maximal relaxation of HCC by 98.3 ± 1.2%. Similarly, the sGC inhibitor blocked the MPSi-NP relaxation. MPSi-NP potentiated the relaxation induced by tadalafil. MPSi-NP increased cGMP levels in HCC strips by 2.6-fold and increased by 3.5-fold the phosphorylation level of the VASP protein, which is a downstream target to PKG. MPSi-NP effectively relaxes RbCC and HCC by activating the sGC-PKG pathway and potentiates the tadalafil response. MPSi-NP could be helpful in conditions where nitric oxide availability is decreased. A topical gel formulation of MPSi-NP could be used as a rescue therapy to treat true non-responders of PDE5Is drugs.
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Affiliation(s)
- Iury A Paz
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil; Group of Bioinorganic, Department of Organic and Inorganic Chemistry, Federal University of Ceará, PO Box 6021, 60440-900, Fortaleza, Ceará, Brazil
| | - Pedro M Silva Filho
- Department of Analytical and Physical Chemistry, Federal University of Ceará, PO Box 6021, Fortaleza, 60440-900, Fortaleza, Ceará, Brazil; Academic Department of Chemistry and Biology, Technologic Federal University of Paraná, 81280-340, Curitiba, Paraná, Brazil
| | - Alexandre S Leitão Junior
- Departament of Urology, Federal University of Ceará, 1290 Pastor Samuel Munguba St., Fortaleza - CE, 60430-372, Fortaleza, Ceará, Brazil
| | - Tatiana Oliveira Pessoa
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil
| | - Renata O Santiago
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil
| | - Nádia Osório de Oliveira
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil
| | - Elisane Longhinotti
- Department of Analytical and Physical Chemistry, Federal University of Ceará, PO Box 6021, Fortaleza, 60440-900, Fortaleza, Ceará, Brazil; Academic Department of Chemistry and Biology, Technologic Federal University of Paraná, 81280-340, Curitiba, Paraná, Brazil
| | - Eduardo H S Sousa
- Group of Bioinorganic, Department of Organic and Inorganic Chemistry, Federal University of Ceará, PO Box 6021, 60440-900, Fortaleza, Ceará, Brazil
| | - Luiz G F Lopes
- Group of Bioinorganic, Department of Organic and Inorganic Chemistry, Federal University of Ceará, PO Box 6021, 60440-900, Fortaleza, Ceará, Brazil
| | - Claudia F Santos
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil
| | - Manassés C Fonteles
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil
| | - Nilberto R F Nascimento
- Department of Physiology and Pharmacology, Superior Institute of Biomedical Sciences, State University of Ceará, 1700. Dr Silas Munguba Av., 60455-900, Fortaleza, Ceará, Brazil.
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Bykov V, Gushchina E, Morozov S, Zhuravskaya N, Kryshen K, Makarov V, Matichin A, Zueva A. Ipidacrine (Axamon), A Reversible Cholinesterase Inhibitor, Improves Erectile Function in Male Rats With Diabetes Mellitus-Induced Erectile Dysfunction. Sex Med 2022; 10:100477. [PMID: 35007992 PMCID: PMC8847829 DOI: 10.1016/j.esxm.2021.100477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/22/2021] [Accepted: 12/01/2021] [Indexed: 12/04/2022] Open
Abstract
Background Management of diabetes mellitus-induced erectile dysfunction (DMED) is challenging because of its insufficient responses to phosphodiesterase type 5 inhibitors. Aim To compare the effects of ipidacrine, a reversible cholinesterase inhibitor, and sildenafil on DMED in a rat model of streptozotocin (STZ)-induced diabetes. Methods Erectile dysfunction (ED) caused by STZ-induced diabetes mellitus was modeled in adult male Wistar rats, which were randomized to 4 groups: untreated diabetic rats, sildenafil (5 mg/kg), ipidacrine (3.6 mg/kg) and ipidacrine (6.7 mg/kg). The test drug (ipidacrine), comparator (sildenafil) or control substance (1% starch solution) were administered orally for 5 days or 14 days. Erectile function was assessed by the change in the maximum intracavernous pressure (ICPmax) following cavernous nerve electrical stimulation. The mean arterial pressure (MAP) was recorded, and the ICPmax/MAP ratio was calculated. Sexual behavior, cholinesterase activity and blood testosterone level tests assessed. Main Outcome Measure The quantitative value of ICPmax/MAP 14 days after the start of administration of the test drug and the comparison drug. Results Animals with STZ-induced diabetes mellitus showed a significant decrease in ICPmax and ICPmax/MAP ratio compared to the intact control group. When ipidacrine was administered to rats with DMED for 14 days, an increase in these indicators was noted. It was proved that ipidacrine at a dose of 6.7 mg/kg has noninferiority compared to sildenafil on the DMED model. Significant increase in ICPmax compared to STZ-control after electrostimulation of the cavernous nerve was recorded following administration of ipidacrine at a dose of 6.7 mg/kg (P < .05) and sildenafil at a dose 5 mg/kg (P < .05). Neither the test drug, nor the comparator were associated with increase in testosterone levels in blood; as well both drugs did not promote activation of sexual behavior. Clinical Implications Ipidacrine may be considered as an effective therapy for DMED but needs to be verified in human investigations. Strengths & Limitations The role of ipidacrine, was firstly demonstrated in rats with DMED. However, the results were obtained in animal experiments, and will be further tested in the study of receptor interactions and the determination of cellular targets. Conclusion This is the first study to show that administration of ipidacrine, the reversible cholinesterase inhibitor, improved erectile function in diabetic rats and these results may be beneficial in further studies using ipidacrine for treatment of DMED, particularly in non-responders to PDE5 inhibitors. Bykov V, Gushchina E, Morozov S, et al. Ipidacrine (Axamon), A Reversible Cholinesterase Inhibitor, Improves Erectile Function in Male Rats With Diabetes Mellitus-Induced Erectile Dysfunction. Sex Med 2022;10:100477.
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Affiliation(s)
- Vladimir Bykov
- N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg, Russia.
| | | | | | | | - Kirill Kryshen
- Institute of Pre-clinical Research Ltd, Leningradskaya Region, Russia
| | - Valery Makarov
- Institute of Pre-clinical Research Ltd, Leningradskaya Region, Russia
| | | | - Alena Zueva
- Institute of Pre-clinical Research Ltd, Leningradskaya Region, Russia
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Higashi Y. Lower urinary tract symptoms/benign prostatic hypertrophy and vascular function: Role of the nitric oxide-phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate pathway. Int J Urol 2017; 24:412-424. [PMID: 28332240 DOI: 10.1111/iju.13336] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/19/2017] [Indexed: 11/30/2022]
Abstract
It is well known that there is an association of lower urinary tract symptoms/benign prostatic hypertrophy with cardiovascular disease, suggesting that lower urinary tract symptoms/benign prostatic hypertrophy is a risk factor for cardiovascular events. Vascular function, including endothelial function and vascular smooth muscle function, is involved in the pathogenesis, maintenance and development of atherosclerosis, leading to cardiovascular events. Vascular dysfunction per se should also contribute to lower urinary tract symptoms/benign prostatic hypertrophy. Both lower urinary tract symptoms/benign prostatic hypertrophy and vascular dysfunction have cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, aging, obesity and smoking. Inactivation of the phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate-nitric oxide pathway causes lower urinary tract symptoms/benign prostatic hypertrophy through an enhancement of sympathetic nervous activity, endothelial dysfunction, increase in Rho-associated kinase activity and vasoconstriction, and decrease in blood flow of pelvic viscera. Both endogenous nitric oxide and exogenous nitric oxide act as vasodilators on vascular smooth muscle cells through an increase in the content of cyclic guanosine 3',5'-monophosphate, which is inactivated by phosphodiesterase type 5. In a clinical setting, phosphodiesterase type 5 inhibitors are widely used in patients with lower urinary tract symptoms/benign prostatic hypertrophy. Phosphodiesterase type 5 inhibitors might have beneficial effects on vascular function through not only inhibition of cyclic guanosine 3',5'-monophosphate degradation, but also increases in testosterone levels and nitric oxide bioavailability, increase in the number and improvement of the function of endothelial progenitor cells, and decrease in insulin resistance. In the present review, the relationships between lower urinary tract symptoms/benign prostatic hypertrophy, the phosphodiesterase type 5-nitric oxide-cyclic guanosine 3',5'-monophosphate pathway, vascular function and cardiovascular outcomes are examined.
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Affiliation(s)
- Yukihito Higashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University Hospital, Hiroshima, Japan.,Divivsion of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
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Azadzoi KM, Yang J, Siroky MB. Neural regulation of sexual function in men. World J Clin Urol 2013; 2:32-41. [PMID: 34707982 PMCID: PMC8547275 DOI: 10.5410/wjcu.v2.i3.32] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 07/30/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Male sexual response is controlled by a series of neurally mediated phenomena regulating libido, motivation, arousal and genital responses such as penile erection and ejaculation. These neural events that occur in a hormonally defined milieu involve different neurophysiological, neurochemical, and neuropsychological parameters controlled by central mechanisms, spinal reflexes and peripheral nervous system. Epidemiologic studies have suggested the high prevalence of male sexual dysfunction worldwide with significant impact on the quality of life of patients suffering from this problem. The incidence of sexual dysfunction is particularly high among men with neurologic disorders. Sexual dysfunction in men, such as loss of sexual desire, erectile dysfunction (ED), changes in arousal, and disturbances in orgasm and ejaculation may involve organic causes, psychological problems, or both. Organic male sexual disorders include a wide variety of neurologic, vasculogenic, neurovascular or hormonal factors that interfere with libido, erection, ejaculation and orgasm. Neurogenic sexual dysfunction may result from a specific neurologic problem or it could be the presenting symptom of a developing neurologic disease. Neurologic ED could result from complications of chronic neurologic disorders, trauma, surgical injury or iatrogenic causes. These etiologic factors and the underlying pathophysiologic conditions could overlap, which should be considered when making a diagnosis and selecting a treatment. A detailed history of physical examination, neurologic disorders, as well as any past history of psychological and psychiatric disturbances, and a thorough neurological examination will provide better understanding of the underlying causes of neurogenic sexual dysfunction. In patients with spinal cord injury, the location of the lesion and the time of onset of injury should be determined. Therapeutic strategies against erectile dysfunction are initiated with the least invasive options using the phosphodiesterase inhibitors. When oral medication options are exhausted, intraurethral and intracavernosal therapies and ultimately vacuum constriction devices and penile implants are considered. Recent basic research has suggested the potential role of stem cell-based therapeutic strategies to protect penile neural integrity and reverse cavernosal neurodegeneration in experimental models. Further insight into the central, spinal and peripheral neural mechanisms of male sexual response may help precise diagnosis and better management of neurogenic sexual dysfunction in men.
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Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide-cyclic GMP pathway in mice. Int J Impot Res 2012; 25:69-73. [PMID: 23034509 DOI: 10.1038/ijir.2012.35] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Phosphodiesterase-9 (PDE9) specifically hydrolyzes cyclic GMP, and was detected in human corpus cavernosum. However, no previous studies explored the selective PDE9 inhibition with BAY 73-6691 in corpus cavernosum relaxations. Therefore, this study aimed to characterize the PDE9 mRNA expression in mice corpus cavernosum, and investigate the effects of BAY 73-6691 in endothelium-dependent and -independent relaxations, along with the nitrergic corpus cavernosum relaxations. Male mice received daily gavage of BAY 73-6691 (or dimethylsulfoxide) at 3 mg kg(-1) per day for 21 days. Relaxant responses to acetylcholine (ACh), nitric oxide (NO) (as acidified sodium nitrite; NaNO2 solution), sildenafil and electrical-field stimulation (EFS) were obtained in corpus cavernosum in control and BAY 73-6691-treated mice. BAY 73-6691 was also added in vitro 30 min before construction of concentration-responses and frequency curves. PDE9A and PDE5 mRNA expression was detected in the mice corpus cavernosum in a similar manner. In vitro addition of BAY 73-6691 neither itself relaxed mice corpus cavernosum nor changed the NaNO2, sildenafil and EFS-induced relaxations. However, in mice treated chronically with BAY 73-6691, the potency (pEC50) values for ACh, NaNO2 and sildenafil were significantly greater compared with control group. The maximal responses (Emax) to NaNO2 and sildenafil were also significantly greater in BAY 73-6691-treated mice. BAY 73-6691 treatment also significantly increased the magnitude and duration of the nitrergic corpus cavernosum relaxations (8-32 Hz). In conclusion, murine corpus cavernosum expresses PDE9 mRNA. Prolonged PDE9 inhibition with BAY 73-6691 amplifies the NO-cGMP-mediated cavernosal responses, and may be of therapeutic value for erectile dysfunction.
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Comparative Relaxing Effects of Sildenafil, Vardenafil, and Tadalafil in Human Corpus Cavernosum: Contribution of Endogenous Nitric Oxide Release. Urology 2009; 74:216-21. [DOI: 10.1016/j.urology.2008.12.056] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2008] [Revised: 11/26/2008] [Accepted: 12/24/2008] [Indexed: 11/20/2022]
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Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. Eur J Pharmacol 2008; 591:189-95. [DOI: 10.1016/j.ejphar.2008.06.055] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2008] [Revised: 06/10/2008] [Accepted: 06/15/2008] [Indexed: 11/22/2022]
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Flores Toque HA, Priviero FBM, Teixeira CE, Perissutti E, Fiorino F, Severino B, Frecentese F, Lorenzetti R, Baracat JS, Santagada V, Caliendo G, Antunes E, De Nucci G. Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction. J Med Chem 2008; 51:2807-15. [PMID: 18393409 DOI: 10.1021/jm701400r] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
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Affiliation(s)
- Haroldo A Flores Toque
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil
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Buhimschi CS, Garfield RE, Weiner CP, Buhimschi IA. The presence and function of phosphodiesterase type 5 in the rat myometrium. Am J Obstet Gynecol 2004; 190:268-74. [PMID: 14749671 DOI: 10.1016/j.ajog.2003.07.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVE Cyclic nucleotide phosphodiesterases (PDEs) are a diverse enzyme group with multiple regulatory properties and wide tissue distribution. Such activity includes cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) breakdown. The type 5 isoform (PDE-5, cGMP specific) is the target of specific antagonists (ie, sildenafil, Viagra). We tested the hypothesis that PDE-5 is present in rat myometrium and modulates myometrial activity. STUDY DESIGN Full-thickness uterine wall was collected from nonpregnant (n=3) and pregnant Sprague-Dawley rats on days 10 (n=4), 17 (n=6), 22 nonlabor (n=5), and 22 during term labor (TL, n=4). Preterm labor (PTL, n=3) was induced in some animals on day 16 with 15 mg/kg mifepristone (RU 486). Tissue samples were prepared for Western blotting using a monoclonal antibody against rodent PDE-5. In a second series, cumulative doses of sildenafil (0.005, 0.05, 0.5, 5 mg/kg, intraperitoneal) were administered and the effect on uterine contractility recorded in vivo during term (TL, n=7) and preterm labor (PTL, n=6). Saline solution-injected rats provided temporal control. Uterine contractility was estimated from intrauterine pressure (IP) measured electronically with a sensor tip pressure catheter. Heart rate was recorded simultaneously using electrodes attached to the chest and connected to the same data acquisition system. RESULTS PDE-5 immunoreactivity was present in the nonpregnant rat uterus and at all gestational times studied, although the expression was unaffected by either pregnancy or the state of labor (preterm or term). A dominant antibody-specific band was identified at 86 kd in the uterine samples, contrasting with lung where the 100-kd PDE-5 isoform was most abundant. Two additional lower molecular weight (55 and 32 kd) bands were also identified as antibody specific. Despite the lack of change in PDE-5 during pregnancy, sildenafil reduced IP during TL and PTL beginning at 0.5 mg/kg. The highest dose of sildenafil reduced IP during both TL and PTL by 45% and 59% of baseline, respectively (two-way analysis of variance, P<.01). This effect was not accompanied by changes in heart rate. CONCLUSION PDE-5 is constitutively present in the rat uterine wall. There was no observed change in the PDE-5 protein expression throughout pregnancy. In contrast to the lung, the uterus expresses an 80-kd PDE-5 isoform. Sildenafil in pharmacologic doses inhibits mechanical uterine activity and might be of benefit if selectively used for treatment of preterm labor.
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Affiliation(s)
- Catalin S Buhimschi
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, CT 06520, USA.
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Hnatyszyn O, Moscatelli V, Rondina R, Costa M, Arranz C, Balaszczuk A, Coussio J, Ferraro G. Flavonoids from Achyrocline satureioides with relaxant effects on the smooth muscle of Guinea pig corpus cavernosum. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2004; 11:366-369. [PMID: 15185852 DOI: 10.1078/0944711041495182] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Ethanol extract of the aerial parts of Achyrocline satureioides (Lam.) DC. (Asteraceae) showed a significant, dose dependent, relaxant effect on the smooth muscle of corpus cavernosum strips, obtained from Guinea pig (65.5 +/- 4.1% of relaxation at the dose of 25.0 mg/ml). Bioassay guided fractionation of this extract furnished two flavonoids, quercetin and quercetin 3-methyl ether, with important vasorelaxing effects on the corpus cavernosum strips (79.8 +/- 8.4 and 66.0 +/- 4.8% of relaxation respectively at the dose of 0.075 mg/ml). Two methyl derivatives of quercetin obtained by synthesis, quercetin 3,7,3',4'-tetramethylether and quercetin 3,5,7,3',4'-pentamethylether, showed similar relaxant effects at the dose of 0.075 mg/ml (86.4 +/- 8.5 and 67.31 +/- 1.4% of relaxation respectively). The results show that the ethanol extract of A. satureioides and the assayed compounds exhibit significant vasorelaxing properties. Additionally, it is shown that the number of methyl groups in the quercetin nucleus has no significant influence on the effectiveness of these compounds.
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Affiliation(s)
- O Hnatyszyn
- Cátedra de Farmacognosia, IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
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Ahn BO, Kang KK, Ahn GJ, Kwon JW, Kim WB, Kang KS, Lee YS. Efficacy of DA-8159, a new PDE5 inhibitor, for inducing penile erection in rabbits with acute spinal cord injury. Int J Impot Res 2003; 15:405-11. [PMID: 14671658 DOI: 10.1038/sj.ijir.3901055] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
DA-8159 is a pyrazolopyrimidinone derivative which exhibits potent and selective phosphodiesterase type 5 (PDE5) inhibition. The aim of this study was to investigate the effects of DA-8159 on inducing a penile erection in rabbits with an acute spinal cord injury (ASCI). DA-8159 was given either orally (1, 3, or 10 mg/kg) or intravenously (0.1 or 0.3 mg/kg) to conscious male albino rabbits with a surgical transection of the spinal cord at the L2-L4 lumbar vertebra or ischemic-reperfusion SCI rabbits. Erection was evaluated in a time-course manner by measuring the length of the uncovered penile mucosa. DA-8159 induced a dose-dependent erection in both transection and ischemic-reperfusion ASCI rabbits. The efficacy of DA-8159 was potentiated by an intravenous injection of sodium nitroprusside, a nitric oxide donor. Potentiation of the effect by nitric oxide donor implies that DA-8159 can enhance the erectile activity during sexual arousal. These results suggest that DA-8159 may be useful for treating erectile dysfunction in patients with an SCI.
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Affiliation(s)
- B O Ahn
- Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul, Korea
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Hnatyszyn O, Moscatelli V, Garcia J, Rondina R, Costa M, Arranz C, Balaszczuk A, Ferraro G, Coussio JD. Argentinian plant extracts with relaxant effect on the smooth muscle of the corpus cavernosum of guinea pig. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2003; 10:669-674. [PMID: 14692728 DOI: 10.1078/0944-7113-00261] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Extracts of different polarity from Baccharis trimera, Haplopappus rigidus Huperzia saururus, Maytenus ilicifolia, Satureja parvifolia and Senecio eriophyton were tested for their relaxant activity on smooth muscle using L-phenylephrine precontracted strips of corpus cavernosum obtained from Guinea pigs. Highly significant and dose dependent results were obtained with the dichloromethane extracts of H. saururus (87% of relaxation at the dose of 10 mg/ml), S. parvifolia (95% of relaxation at 2.5 mg/ml) and S. eriophyton (94% of relaxation at 5 mg/ml). Similar effects were observed with the methanol extracts of H. saururus (88% of relaxation at 10 mg/ml) and S. parvifolia (84% of relaxation at 10 mg/ml). These results were comparable to those obtained with the dichloromethane and methanol extracts of the well known Mexican species Turnera diffusa. Moreover, the aqueous extract of H. rigidus and the aqueous and methanol extracts of S. eriophyton were highly effective in a dose dependent manner (more than 90% of relaxation at the dose of 10 mg/ml). Significant results, but with a lower overall relaxant activity (about 70% of relaxation at 10 mg/ml), could also be obtained with the aqueous extract of S. parvifolia and with the dichlormethane and methanol extracts of B. trimera and M. ilicifolia. The positive controls with Sildenafil citrate at doses ranging from 0.35 to 35 microg/ml yielded moderate effects (up to 46% of relaxation at 35 microg/ml). The effects observed in the present study seem to validate the folk medicinal use of the tested plants and open new ways in the search for natural products with vasodilatory effects.
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Affiliation(s)
- O Hnatyszyn
- Cátedra de Farmacognosia, IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
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Kang KK, Ahn GJ, Ahn BO, Yoo M, Kim WB. DA-8159, a new PDE5 Iihibitor, induces penile erection in conscious and acute spinal cord injured rabbits. Eur Urol 2003; 43:689-95. [PMID: 12767372 DOI: 10.1016/s0302-2838(03)00153-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES DA-8159 is a pyrazolopyrimidinone derivative showing potent and selective phosphodiesterase 5 (PDE5) inhibition. In the previous study, DA-8159 induced a dose-dependent increase in the intracavernous pressure (ICP) in anaesthetized dogs. The aim of this study was to investigate the effects of DA-8159 on penile erection in conscious and acute spinal cord injured (ASCI) rabbits. METHODS DA-8159 was given orally (0.3 to 10mg/kg) to normal rabbits and ASCI rabbits with a surgical transection of the spinal cord at the L2-L4 lumbar vertebra or ischemic-reperfusion. The erection was evaluated in a time-course manner by measuring the length of the uncovered penile mucosa in the absence or presence of intravenous sodium nitroprusside (SNP), a nitric oxide (NO) donor. RESULTS DA-8159 induced a dose-dependent penile erection in both the conscious and ASCI rabbits. The efficacy of DA-8159 was potentiated and the effective doses were significantly decreased by an intravenous injection of SNP. Potentiation of the effect by a nitric oxide donor implies that DA-8159 can enhance the erectile activity during sexual arousal. CONCLUSION These results demonstrate that DA-8159 may be a useful treatment option for erectile dysfunction in patients with or without a spinal cord injury, but further evaluation of the effects of DA-8159 on humans must be performed.
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Affiliation(s)
- Kyung Koo Kang
- Research Laboratories of Dong-A Pharmaceutical Company, 47-5 Sanggal, Kiheung, Youngin, Kyunggi, 449-900 South Korea.
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Kimura M, Higashi Y, Hara K, Noma K, Sasaki S, Nakagawa K, Goto C, Oshima T, Yoshizumi M, Chayama K. PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers. Hypertension 2003; 41:1106-10. [PMID: 12695418 DOI: 10.1161/01.hyp.0000068202.42431.cc] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Smoking is associated with endothelial dysfunction. The purpose of this study was to determine the effect of sildenafil, an inhibitor of phosphodiesterase type 5 (PDE5), on endothelial function in smokers. We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after oral sildenafil administration (100 mg) with a strain-gauge plethysmograph in 10 young healthy male smokers and 10 young healthy male nonsmokers. FBF response to ACh was lower in smokers than in nonsmokers. The vasodilatory effects of SNP were similar in both groups. Sildenafil increased the FBF response to ACh from 9.3+/-2.0 to 12.5+/-3.5 mL/min per 100 mL tissue in smokers and from 12.6+/-5.6 to 19.6+/-8.4 mL/min per 100 mL tissue in nonsmokers, and it increased the response to SNP from 13.3+/-3.9 to 15.1+/-4.3 mL/min per 100 mL tissue in smokers and from 14.8+/-5.2 to 18.4+/-6.0 mL/min/100 mL tissue in nonsmokers (P<0.05 for all). The ratio of maximal ACh-stimulated FBF expressed as a ratio of maximal SNP-stimulated FBF significantly increased after administration of sildenafil in both groups. Infusion of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, abolished sildenafil-induced augmentation of the FBF response to ACh in both groups. The findings suggest that endothelial function is impaired in smokers compared with that in nonsmokers, that inhibition of PDE5 by sildenafil significantly increases nitric oxide-mediated vasodilation, and that the activities of PDE5 in smokers and nonsmokers may be similar.
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Affiliation(s)
- Masashi Kimura
- Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
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