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Hennenberg M, Acevedo A, Wiemer N, Kan A, Tamalunas A, Wang Y, Yu Q, Rutz B, Ciotkowska A, Herlemann A, Strittmatter F, Stief CG, Gratzke C. Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction is Sufficient to Replace α 1 -Adrenergic Tension in the Human Prostate. Prostate 2017; 77:697-707. [PMID: 28116771 DOI: 10.1002/pros.23293] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 12/05/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia may be caused by prostate smooth muscle contraction. Although α1 -blockers may improve symptoms by prostate smooth muscle relaxation, their efficacy is limited. This may be explained by non-adrenergic mediators causing contraction in parallel to α1 -adrenoceptors. However, little is known about the relevance and cooperative actions of non-adrenergic mediators in the prostate. METHODS Prostate tissues were obtained from radical prostatectomy (n = 127 patients). Contractile responses were studied in an organ bath. RESULTS Endothelin-1 and noradrenaline induced contractions of similar magnitude (116 ± 23 and 117 ± 18% of KCl-induced contractions). Endothelin-2- and -3-induced maximum contractions of 63 ± 8.6 and 71 ± 19% of KCl, while contractions by the thromboxane analog U46619 amounted up to 63 ± 9.4%. Dopamine-induced contractions averaged to 22 ± 4.5% of KCl, while maximum contractions by serotonin, histamine, and carbachol stayed below 10% of KCl-induced. While noradrenaline-induced contractions were inhibited by tamsulosin (300 nM), endothelin-1-, -2-, or -3-induced contraction were not. No additive effects were observed if endothelins and noradrenaline were applied consecutively to the same samples. If endothelin-1 was applied after U46619, resulting tension (172 ± 43% of KCl) significantly exceeded noradrenaline-induced contraction. Tensions following combined application of endothelin-2 or -3 with U46619 stayed below noradrenaline-induced contractions. Tension following combined application of all three endothelins with U46619 resembled maximum noradrenaline-induced tone. CONCLUSIONS Contractions following concomitant confrontation of human prostate tissue with noradrenaline and endothelin-1 are not additive. Endothelin-1 is sufficient to induce a smooth muscle tone resembling that of noradrenaline. This may replace lacking α1 -adrenergic tone under therapy with α1 -blockers, explaining the limited efficacy of α1 -blockers in LUTS treatment. Contractions by thromboxane and endothelin-1 may be additive, and may exceed α1 -adrenergic tone. Prostate 77:697-707, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Martin Hennenberg
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Alice Acevedo
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Nicolas Wiemer
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Aysenur Kan
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | | | - Yiming Wang
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Qingfeng Yu
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Beata Rutz
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Anna Ciotkowska
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Annika Herlemann
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | | | - Christian G Stief
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
| | - Christian Gratzke
- Department of Urology, Ludwig-Maximilians University, Munich, Germany
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Ventura S, Oliver VL, White CW, Xie JH, Haynes JM, Exintaris B. Novel drug targets for the pharmacotherapy of benign prostatic hyperplasia (BPH). Br J Pharmacol 2011; 163:891-907. [PMID: 21410684 DOI: 10.1111/j.1476-5381.2011.01332.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) is the major cause of lower urinary tract symptoms in men aged 50 or older. Symptoms are not normally life threatening, but often drastically affect the quality of life. The number of men seeking treatment for BPH is expected to grow in the next few years as a result of the ageing male population. Estimates of annual pharmaceutical sales of BPH therapies range from $US 3 to 10 billion, yet this market is dominated by two drug classes. Current drugs are only effective in treating mild to moderate symptoms, yet despite this, no emerging contenders appear to be on the horizon. This is remarkable given the increasing number of patients with severe symptoms who are required to undergo invasive and unpleasant surgery. This review provides a brief background on prostate function and the pathophysiology of BPH, followed by a brief description of BPH epidemiology, the burden it places on society, and the current surgical and pharmaceutical therapies. The recent literature on emerging contenders to current therapies and novel drug targets is then reviewed, focusing on drug targets which are able to relax prostatic smooth muscle in a similar way to the α(1) -adrenoceptor antagonists, as this appears to be the most effective mechanism of action. Other mechanisms which may be of benefit are also discussed. It is concluded that recent basic research has revealed a number of novel drug targets such as muscarinic receptor or P2X-purinoceptor antagonists, which have the potential to produce more effective and safer drug treatments.
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Affiliation(s)
- S Ventura
- Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
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Effects of Phosphodiesterase Inhibitors on Contraction Induced by Endothelin-1 of Isolated Human Prostatic Tissue. Urology 2009; 73:1397-401. [DOI: 10.1016/j.urology.2008.11.041] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Revised: 11/10/2008] [Accepted: 11/26/2008] [Indexed: 11/18/2022]
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Uckert S, Sormes M, Kedia G, Scheller F, Knapp WH, Jonas U, Stief CG. Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue. Urology 2008; 71:526-30. [PMID: 18342202 DOI: 10.1016/j.urology.2007.10.051] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 09/21/2007] [Accepted: 10/25/2007] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To further evaluate the mechanism of action of phosphodiesterase (PDE) inhibitors on the human prostate, the effects of PDE4 and PDE5 inhibitors on the tension induced by norepinephrine (NE) and on the intracellular levels of cyclic nucleotides in isolated human prostatic tissue were investigated. METHODS Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil and the PDE4 inhibitors rolipram and RP 73401 on the tension induced by NE (40 microM) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays. RESULTS The tension induced by NE was dose dependently reversed by the drugs with the following rank order of efficacy: tadalafil greater than RP 73401 greater than rolipram greater than or equal to vardenafil greater than sildenafil. The maximal reversion of tension values ranged from 52.3% (tadalafil) to 17% (sildenafil). Of the PDE inhibitors, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP 73401 (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil, and sildenafil (28-fold, 12-fold, and 3-fold, respectively). CONCLUSIONS Our results have demonstrated that drugs interfering with the cyclic nucleotide-mediated pathways can reverse the tension induced by NE in isolated prostatic tissue and elevate cyclic adenosine monophosphate and cyclic guanosine monophosphate. Our findings serve to explain how PDE inhibitors can affect symptoms of lower urinary tract symptoms and benign prostatic hyperplasia.
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Affiliation(s)
- Stefan Uckert
- Department of Urology, Hannover Medical School, Hannover, Germany.
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Gur S, Kadowitz PJ, Hellstrom WJG. Guide to Drug Therapy for Lower Urinary Tract Symptoms in Patients with Benign Prostatic Obstruction. Drugs 2008; 68:209-29. [DOI: 10.2165/00003495-200868020-00005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Abstract
Lower urinary tract symptoms (LUTS) are commonly divided into storage, voiding, and postmicturition symptoms, and may occur in both men and women. Male LUTS have historically been linked to benign prostatic hyperplasia (BPH), but are not necessarily prostate related. The focus of treatment for LUTS has thus shifted from the prostate to the bladder and other extraprostatic sites. LUTS include symptoms of the overactive bladder (OAB), which are often associated with detrusor overactivity. Treatment for LUTS suggestive of BPH has traditionally involved the use of alpha(1)-adrenoceptor (AR) antagonists; 5alpha-reductase inhibitors; and phytotherapy-however, several new therapeutic principles have shown promise. Selective beta(3)-adrenoceptor agonists and antimuscarinics are potentially useful agents for treating LUTS, particularly for storage symptoms secondary to outflow obstruction. Other agents of potential or actual importance are antagonists of P2X(3) receptors, botulinum toxin type A, endothelin (ET)-converting enzyme inhibitors, and drugs acting at vanilloid, angiotensin, and vitamin D(3) receptor sites. Drugs interfering with the nitric oxide/cGMP-cAMP pathway, Rho-kinase and COX inhibitors, as well as drugs targeting receptors and mechanisms within the CNS, are also of interest and deserving of further study for the treatment of LUTS.
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Affiliation(s)
- K-E Andersson
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA.
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Ückert S, Hedlund P, Andersson KE, Truss MC, Jonas U, Stief CG. Update on Phosphodiesterase (PDE) Isoenzymes as Pharmacologic Targets in Urology: Present and Future. Eur Urol 2006; 50:1194-207; discussion 1207. [DOI: 10.1016/j.eururo.2006.05.025] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2004] [Accepted: 05/08/2006] [Indexed: 01/23/2023]
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Kedia G, Uckert S, Scheller F, Chigogidze T, Managadze L, Jonas U, Truss MC. In vitro functional responses of isolated normal human prostatic tissue to compounds interacting with the cyclic guanosine monophosphate pathway. Urology 2006; 67:1292-7. [PMID: 16678889 DOI: 10.1016/j.urology.2005.12.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2005] [Revised: 11/07/2005] [Accepted: 12/01/2005] [Indexed: 11/28/2022]
Abstract
OBJECTIVES To examine the effects of some nitric oxide-donating agents, as well as the C-type natriuretic peptide (CNP), on isolated human prostatic tissue. To date, guanylyl cyclases and cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterases represent important target proteins for the development of new drugs for the treatment of lower urinary tract symptoms and benign prostatic hyperplasia. METHODS Using the organ bath technique, the effects of sodium nitroprusside, S-nitrosoglutathione, S-nitrosocysteine, linsidomine, and CNP (1 nM to 1.0/10 microM) on the tension induced by norepinephrine of prostatic tissue strips were investigated. The tissue was also exposed to three different concentrations of the drugs, and the production of cGMP and cyclic adenosine monophosphate (cAMP) was determined. RESULTS The tension induced by 40 microM norepinephrine of the isolated prostatic tissue was dose dependently reversed by the drugs. The rank order of potency was sodium nitroprusside more than S-nitrosoglutathione more than linsidomine more than S-nitrosocysteine, which was equal to CNP (1 microM). The reversal of tension induced by the greatest drug concentrations ranged from 50% relaxation with sodium nitroprusside to 42% relaxation with CNP. The relaxing effects of the drugs were paralleled by a 2-fold to 40-fold and 2-fold to 45-fold increase in tissue levels of cAMP and cGMP, respectively. CONCLUSIONS Our results provide further evidence that cGMP and cAMP are involved in the control of the normal function of human prostatic smooth muscle. Our findings may provide new strategies for future therapeutics used in the treatment of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia.
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Affiliation(s)
- Giorgi Kedia
- Department of Urology, Hannover Medical School, Hannover, Germany.
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Uckert S, Oelke M, Stief CG, Andersson KE, Jonas U, Hedlund P. Immunohistochemical Distribution of cAMP- and cGMP-Phosphodiesterase (PDE) Isoenzymes in the Human Prostate. Eur Urol 2006; 49:740-5. [PMID: 16460876 DOI: 10.1016/j.eururo.2005.12.050] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2005] [Accepted: 12/23/2005] [Indexed: 11/18/2022]
Abstract
OBJECTIVES With the introduction of sildenafil citrate (Viagra), the concept of phosphodiesterase (PDE) inhibition has gained tremendous interest in the field of urology. Cyclic nucleotide second messengers cGMP and cAMP have been assumed to be involved in the control of the normal function of the prostate. The aim of the present study was to evaluate by means of immunohistochemistry the expression and distribution of some cAMP- and cGMP-PDE isoenzymes in the prostate. MATERIAL & METHODS Cryostat sections (10 microM) of formaldehyde-fixated tissue segments excised from the transition zone of human prostates were incubated with primary antibodies directed against the PDE isoenzymes 3, 4, 5, and 11. Then, sections were exposed to either fluorescein isothiocyanate- (FITC) or Texas Red- (TR) labeled secondary antibodies and visualization was commenced by means of laser fluorescence microscopy. RESULTS TR-immunofluorescence indicating the presence of PDE4 (cAMP-PDE) was abundantly observed in the fibromuscular stroma as well as in glandular structures of the transition zone. In contrast to the distribution of PDE4, immunoactivity indicating PDE5 (cGMP-PDE) and 11 (dual substrate PDE) was mainly observed in glandular and subglandular areas. No immunostaining for PDE3 (cGMP-inhibited PDE) was detected. CONCLUSION Our results confirm the presence of PDE isoenzymes 4, 5 and 11 in the transition zone of the human prostate and present evidence that these isoenzymes are not evenly distributed. These findings are in support of the hypothesis that there might be a rationale for the use of PDE inhibitors in the pharmacotherapy of BPH and LUTS.
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Affiliation(s)
- Stefan Uckert
- Hannover Medical School, Department of Urology, Hannover, Germany.
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Andrzejewska A, Dlugosz JW, Augustynowicz A. Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats. World J Gastroenterol 2005; 11:1115-21. [PMID: 15754391 PMCID: PMC4250700 DOI: 10.3748/wjg.v11.i8.1115] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the effect of non-selective ETA/B (LU 302872) and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.
METHODS: Male Wistar rats with caerulein-induced AP, lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w. of each antagonist. Edema, inflammatory infiltration, necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase, and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.
RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P<0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P<0.05) vs 0.58±0.06 in untreated AP. The non-selective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P<0.01) vs 1.88±0.08 in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum, autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups. %FAT/TPT in untreated AP increased about four times (18.4±3.8 vs 4.8±1.3 in control group without AP, P<0.001). Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.
CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.
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Affiliation(s)
- Anna Andrzejewska
- Department of Medical Pathomorphology, Medical University of Bialystok, Waszygton Str. 13, 15-269 Białystok, Poland.
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Andrzejewska A, Dlugosz JW. The endothelin-1 receptor antagonists ameliorate histology and ultrastructural alterations in the pancreas and decrease trypsinogen activation in severe taurocholate pancreatitis in rats. Int J Exp Pathol 2004; 84:221-9. [PMID: 14690481 PMCID: PMC2517562 DOI: 10.1111/j.1365-2613.2003.00359.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The role of potent vasoconstrictor endothelin-1 (ET-1) in acute pancreatitis (AP) remains controversial. The aim was to compare the effect of nonselective ET RA/B (LU-302872) and selective ET RA (LU-302146) antagonists on pancreatic histology, ultrastructure and trypsinogen activation in severe taurocholate AP in rats. Male Wistar rats with AP were treated with an intraperitoneous injection of 1, 5 and 10 mg/kg of body weight of each antagonist at 0, 6, 12 and 18 h after taurocholate administration. After 24 h, the samples of pancreases were taken for histological and ultrastructural examinations and for assessment of trypsinogen activation. Both antagonists, at all investigated doses, decreased the damage to the acinar cells detected in the light microscope and ultrastructurally. Trypsinogen activation increased to 29.7 +/- 3.9% in the AP untreated in comparison to the control group [12.7 +/- 1.4% (P<0.001)]. This increase was attenuated to 13.8 +/- 2.2% in AP treated with a high dose of the nonselective antagonist and to 8.4 +/- 1.7% with low dose of selective antagonist. The obtained results indicate that ET-1 could participate in the damage to the pancreas during AP. Both antagonists of ET-1 receptors exerted a similar beneficial effect on the morphological changes of the pancreas in AP. One of the probable mechanism could be the attenuation of trypsinogen activation.
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Affiliation(s)
- Anna Andrzejewska
- Department of Clinical Pathomorphology, Medical University of Bialystok, Bialystok, Poland.
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Hocher B, Kalk P, Slowinski T, Godes M, Mach A, Herzfeld S, Wiesner D, Arck PC, Neumayer HH, Nafz B. ETA receptor blockade induces tubular cell proliferation and cyst growth in rats with polycystic kidney disease. J Am Soc Nephrol 2003; 14:367-76. [PMID: 12538737 DOI: 10.1097/01.asn.0000042165.63601.65] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Tissue concentrations of ET-1 are markedly elevated in the kidneys of Han:Sprague-Dawley (Han:SPRD) rats, a model of human autosomal dominant polycystic kidney disease (ADPKD). This study analyzed whether disease progression might be attenuated by endothelin receptor antagonists. Heterozygous Han:SPRD rats received an ETA receptor antagonist (LU 135252), a combined ETA/ETB receptor antagonist (LU 224332), or placebo for 4 mo. Glomerulosclerosis, protein excretion, and GFR remained unchanged, whereas interstitial fibrosis was enhanced by both compounds. BP was not reduced by both compounds in Han:SPRD rats. Renal blood flow (RBF) decreased in ADPKD rats treated with the ETA receptor antagonist. Long-term ETA receptor blockade furthermore increased markedly the number of renal cysts (ADPKD rats, 390 +/- 119 [cysts/kidney section +/- SD]; LU 135252-treated APKD rats, 1084 +/- 314; P < 0.001), cyst surface area (ADPKD rats, 7.97 +/- 2.04 [% of total section surface +/- SD]; LU 135252-treated ADPKD rats, 33.83 +/- 10.03; P < 0.001), and cell proliferation of tubular cells (ADPKD rats, 42.2 +/- 17.3 [BrdU-positive cells/1000 cells]; LU 135252-treated ADPKD rats, 339.4 +/- 286.9; P < 0.001). The additional blockade of the ETB receptor attenuated these effects in Han:SPRD rats. Both endothelin receptor antagonists had no effect on BP, protein excretion, GFR, and kidney morphology in Sprague-Dawley rats without renal cysts. It is concluded that ETA receptor blockade enhances tubular cell proliferation, cyst number, and size and reduces RBF in Han:SPRD rats. This is of major clinical impact because endothelin receptor antagonists are upcoming clinically used drugs.
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Affiliation(s)
- Berthold Hocher
- Department of Nephrology, University Hospital Charité, Humboldt University of Berlin, D-10098 Berlin, Germany.
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Ventura S, Salamoussa A. Big endothelin-1 but not endothelin-1 is present in the smooth muscle stroma of the prostate gland of the rat. J Anat 2002; 200:153-8. [PMID: 11895113 PMCID: PMC1570671 DOI: 10.1046/j.0021-8782.2001.00015.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Immunohistochemical techniques were employed to localize the presence of endothelins in the mature rat prostate gland. Immunoreactivity for big endothelin-1 but not endothelin-1 was observed in the fibromuscular stroma of the rat prostate gland. No immunoreactivity was seen in the glandular epithelium. Double staining procedures showed big endothelin-1 immunoreactivity to be co-localized with alpha-actin immunoreactivity. The stroma of the prostate gland also contained nerve fibres coursing through it which are immunopositive for tyrosine hydroxylase. These results suggest that big endothelin-1 but not endothelin-1 is co-localized with alpha-actin in the smooth muscle cells of the rat prostate gland. This implies that endothelin-1 is synthesized on demand from big endothelin-1 in the fibromuscular stroma of the rat prostate.
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Affiliation(s)
- S Ventura
- Department of Pharmacology, Victorian College of Pharmacy, Monash University, Clayton, Vic, Australia.
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CHARACTERIZATION AND FUNCTIONAL RELEVANCE OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE ISOENZYMES OF THE HUMAN PROSTATE. J Urol 2001. [DOI: 10.1097/00005392-200112000-00127] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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CHARACTERIZATION AND FUNCTIONAL RELEVANCE OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE ISOENZYMES OF THE HUMAN PROSTATE. J Urol 2001. [DOI: 10.1016/s0022-5347(05)65621-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Dao HH, Lemay J, de Champlain J, deBlois D, Moreau P. Norepinephrine-induced aortic hyperplasia and extracellular matrix deposition are endothelin-dependent. J Hypertens 2001; 19:1965-73. [PMID: 11677361 DOI: 10.1097/00004872-200111000-00006] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin has been suggested to be a mediator of hypertrophy. OBJECTIVE To examine the involvement of endothelin in maintaining the growth response induced by exogenous norepinephrine. DESIGN AND METHODS Rats were treated with norepinephrine (2.5 microg/Kg per min subcutaneously) for 2 and 4 weeks, alone or in association with the selective endothelin-A (ETA) receptor antagonist, darusentan (LU135252, 30 mg/Kg per day orally) for weeks 3 and 4. RESULTS Increases in medial cell number and accumulation of collagen and elastin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be related to enhanced pressure variability in addition to direct effects of norepinephrine. Inhibition of ETA receptors by darusentan reversed aortic alterations produced by infusion of norepinephrine. Evaluation of medial apoptosis did not reveal any significant change in any group at 4 weeks. CONCLUSIONS Antagonism of ETA receptors effectively and rapidly reversed norepinephrine-induced aortic structural and compositional changes, suggesting a central role of endothelin in mediating this response. Thus, ETA receptor antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations.
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Affiliation(s)
- H H Dao
- Faculty of Pharmacy and bDepartment of Physiology, Faculty of Medicine, University of Montreal, Canada
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Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, Bauer C, Neumayer HH, Raschack M. Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron Clin Pract 2001; 87:161-9. [PMID: 11244312 DOI: 10.1159/000045906] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Diabetic nephropathy is the leading cause of end-stage renal disease in European countries and is associated with an enhanced renal synthesis of endothelin (ET)-1. ETs are - beside their potent vasoconstrictor properties - very potent profibrotic acting paracrine hormones especially in the kidney. METHODS We analyzed in rats with streptozotocin-induced diabetes the effects of an ETA-type (ETA) receptor antagonist (LU 135252) in comparison to a combined ETA/ETB receptor antagonist (LU 224332) on the expression of interstitial and glomerular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry using a computer-aided image analysis system. Global glomerular matrix deposition was analyzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excretion. The diabetic rats were treated for 36 weeks. RESULTS Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive material within the glomeruli. The expression of glomerular fibronectin and type IV collagen was increased 36 weeks after induction of diabetes. The overexpression of these two matrix proteins within the glomeruli of diabetic rats was completely abolished by both ET receptor antagonists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treatment. CONCLUSION The present study indicates that ETA receptor antagonists as well as combined ETA/ETB receptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyperglycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new approach in the treatment of diabetic nephropathy.
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Affiliation(s)
- B Hocher
- Department of Nephrology, Charité, Humboldt University of Berlin, Germany.
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Braun C, Conzelmann T, Vetter S, Schaub M, Back WE, Kirchengast M, Tullius SG, Schnülle P, van der Woude FJ, Rohmeiss P. Treatment with a combined endothelin A/B-receptor antagonist does not prevent chronic renal allograft rejection in rats. J Cardiovasc Pharmacol 2000; 36:428-37. [PMID: 11026642 DOI: 10.1097/00005344-200010000-00003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
A markedly increased expression of endothelin (ET)-1 has been observed in renal allografts with chronic rejection, one of the most common causes of kidney graft loss. In this study we investigated the effect of treatment with a combined ET-A/B-receptor antagonist on the course of chronic renal allograft rejection. Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-to-Lewis isografts and uninephrectomized Lewis rats served as controls. Animals were treated with either the oral combined ET-A/B-receptor antagonist LU224332 (20 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light-microscopic evaluation and immunohistochemical assessment of cell-surface markers. Treatment with LU224332 did not improve survival after 24 weeks (0.47 vs. 0.38; p > 0.05 by log-rank test), nor did it have an influence on blood pressure, creatinine clearance, or proteinuria. Combined ET-A/B-receptor blockade was associated with a reduction of expression of cell-surface markers for macrophages (EDI), T-cells (R73), and major histocompatibility complex (MHC) II (F17-23-2), but did not lead to an improvement of histologic changes of chronic allograft rejection. Our data show that blocking both ET-A- and -B receptors, in opposition to a previously published beneficial effect of selective ET-A blockade, does not prevent the progression of chronic renal allograft rejection and does not prolong survival in this model. Functional integrity of the ET-B receptor therefore seems to play an important role in the nephroprotection provided by selective ET-A-receptor antagonists in chronic renal allograft nephropathy.
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Affiliation(s)
- C Braun
- V. Department of Medicine (Nephrology/Endocrinology), University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
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Salamoussa A, Lau WA, Pennefather JN, Ventura S. The contractile effects of endothelins on the smooth muscle of the rat prostate gland. Eur J Pharmacol 2000; 403:139-45. [PMID: 10969155 DOI: 10.1016/s0014-2999(00)00580-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Endothelin-1 elicited tonic contractions of rat prostatic smooth muscle that were unaffected by prazosin (0.5 microM), tetrodotoxin (1 microM) or guanethidine (10 microM). The rank order of potency of the endothelin isopeptides was endothelin-1>endothelin-2> or =endothelin-3. Sarafotoxin S6B was approximately equipotent with endothelin-1 in eliciting tonic contractions, but neither of the selective endothelin ET(B) receptor-agonists, sarafotoxin S6C (0.1 nM-0.3 microM) and BQ3020 (Ac-[Ala (11,15)]endothelin-1(6-21); 0.1 nM-0.3 microM), affected prostatic smooth muscle tone. The selective endothelin ET(A) receptor antagonist, BQ123 (cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp; 1 microM), attenuated responses to endothelin-1, -2 and -3, while the non-selective endothelin receptor antagonist bosentan (1 microM) and the selective endothelin ET(B) receptor antagonist BQ788, (Dmpc-gamma-MeLeu(9)-D-Trp(l-CO(2)CH(3))-D-Nle-OH; 1 microM) attenuated responses to endothelin-3 only. Contractions induced by exogenous administration of noradrenaline were unaffected by preincubation of tissues in BQ123 (1 microM) indicating the selectivity of this antagonist. These data suggest that endothelins mediate contractions of the rat prostate by action at endothelin ET(A) receptors.
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Affiliation(s)
- A Salamoussa
- Department of Pharmacology, Monash University, PO Box 13E, 3800, Victoria, Australia
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Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG, Riecken EO, Schuppan D. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 2000; 118:1169-78. [PMID: 10833492 DOI: 10.1016/s0016-5085(00)70370-2] [Citation(s) in RCA: 120] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Endothelin 1 induces contraction, proliferation, and collagen synthesis of hepatic stellate cells in vitro, which may be mediated via the endothelin A receptor. It is unknown if specific blockade of the endothelin A receptor inhibits hepatic fibrosis in vivo. METHODS Groups of 10-20 rats with bile duct occlusion were treated with the nonpeptide endothelin-A receptor antagonist LU 135252 at 80 mg. kg(-1). day(-1) from week 1-6 or from week 4-6, or with LU at 10 mg. kg(-1). day(-1) from week 1-6. Animals with bile duct occlusion alone and sham-operated rats without or with LU at 80 mg. kg(-1). day(-1) over 6 weeks served as controls. After 6 weeks, parameters of fibrogenesis were determined. RESULTS LU treatment led to improved histology, paralleled by a dose-dependence up to 60% reduction of liver collagen, even when administered at an advanced fibrosis stage. This was accompanied by a decreased messenger RNA of hepatic procollagen alpha1(I) and tissue inhibitor of metalloproteinase 1, 2 major effectors of fibrosis, and of serum procollagen type III, a surrogate marker of liver fibrogenesis. CONCLUSIONS Selective endothelin-A receptor blockade can dramatically reduce collagen accumulation in rat secondary biliary fibrosis, a model refractory to most potential antifibrotic agents. Endothelin-A receptor antagonists are promising antifibrotic agents in chronic liver disease.
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MESH Headings
- Administration, Oral
- Alanine Transaminase/blood
- Alkaline Phosphatase/blood
- Animals
- Ascites/drug therapy
- Ascites/metabolism
- Aspartate Aminotransferases/blood
- Bilirubin/blood
- Cholestasis/drug therapy
- Cholestasis/metabolism
- Cholestasis/pathology
- Collagen/analysis
- Collagen/biosynthesis
- DNA, Complementary
- Disease Models, Animal
- Endothelin Receptor Antagonists
- Endothelin-1/analysis
- Female
- Hydroxyproline/analysis
- Hypertension, Portal/drug therapy
- Hypertension, Portal/metabolism
- Hypertension, Portal/pathology
- Jaundice/drug therapy
- Jaundice/metabolism
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Experimental/drug therapy
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/pathology
- Organ Size
- Phenylpropionates/pharmacology
- Pyrimidines/pharmacology
- RNA, Messenger/analysis
- Rats
- Rats, Wistar
- Receptor, Endothelin A
- Receptor, Endothelin B
- Receptors, Endothelin/analysis
- Receptors, Endothelin/metabolism
- Tissue Inhibitor of Metalloproteinase-1/genetics
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Affiliation(s)
- J J Cho
- Department of Gastroenterology, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany
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Schweda F, Blumberg FC, Schweda A, Kammerl M, Holmer SR, Riegger GA, Pfeifer M, Krämer BK. Effects of chronic hypoxia on renal renin gene expression in rats. Nephrol Dial Transplant 2000; 15:11-5. [PMID: 10607761 DOI: 10.1093/ndt/15.1.11] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The effects of hypoxia on renin secretion and renin gene expression have been controversial. In recent studies, we have demonstrated that acute hypoxia of 6 h duration caused a marked stimulation of renin secretion and renal renin gene expression. This hypoxia-induced stimulation of the renin-angiotensin system might contribute, for example, to the progression of chronic renal failure and to the development of hypertension in the sleep-apnoea syndrome. For this reason, we were interested in the more chronic effects of hypoxia on renal renin gene expression and its possible regulation. METHODS Male rats were exposed to chronic normobaric hypoxia (10% O(2)) for 2 and 4 weeks. Additional groups of rats were treated with an endothelin ET(A) receptor antagonist, LU135252, or a NO donor, molsidomine, respectively. Systolic blood pressure and right ventricular pressures were measured. Renal renin, endothelin-1 and endothelin-3 gene expression were quantitated using RNAase protection assays. RESULTS During chronic hypoxia, haematocrit increased to 72+/-2%, and right ventricular pressure increased by a mean of 26 mmHg. Renal renin gene expression was halved during 4 weeks of chronic hypoxia. This decrease was reversed by endothelin receptor blockade (105 or 140% of baseline values after treatment for weeks 3-4 or 1-4). Furthermore, there was a trend of increasing renal endothelin-1 gene expression (to 173% of baseline values) after 4 weeks of hypoxia. Systolic blood pressure increased moderately during 4 weeks of chronic hypoxia from 129+/-2 to 150+/-4 mmHg. This blood pressure increase was higher in rats treated for 4 weeks with an endothelin receptor antagonist (196+/-11 mmHg). CONCLUSIONS Chronic hypoxia (in contrast to acute hypoxia) suppresses renal renin gene expression. This inhibition presumably is mediated by endothelins.
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Affiliation(s)
- F Schweda
- Klinik und Poliklinik für Innere Medizin II, Klinikum der Universität Regensburg, Regensburg, Germany
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