AbstractObjectivesEndothelin (ET) is a strong constrictor of smooth muscle structures. The relevance of Endothelin‐A receptors in the bladder was demonstrated in several in vitro studies. The aim of this functional study was to evaluate the acute effect of the selective ET‐A‐antagonist LU 302146 (LU) on neurostimulation‐induced bladder contractions in vivo.MethodsEight male mini pigs were anesthesized. The bladder was exposed and a double lumen catheter was inserted to perform intravesical pressure (pves) measurements. Laminectomy was performed for sacral anterior root stimulation (SARS) of S2. Four animals received the selective ET‐A‐antagonist LU, three atropine and one animal was treated with vehicle. Pves was recorded before and after drug administration as well as before and during neurostimulation. At the end of each LU trial, a supplementary application of 4 mg atropine was administered followed by a final SARS.ResultsIn all experiments reproducible pves values were elicited during electrostimulation before administration of the test substance. The selective ET‐A‐antagonist reduced stimulation‐induced bladder contraction by a mean of 57%. Additional administration of atropine inhibited the detrusor contraction almost completely during SARS. The vehicle had no effect on bladder contraction.ConclusionsIn the presented animal model, ET‐1 inhibition with the selective ET receptor‐A‐antagonist LU 302146 decreases stimulation‐induced bladder contraction in vivo. The results suggest that the selective ET‐A antagonist LU acts on the atropine‐resistant component of efferent detrusor activation since additional administration of atropine almost completely abolish detrusor contraction. This observation in addition to the involvement of ET‐1 in bladder smooth muscle proliferation, raises the possibility that ET‐receptor antagonists might be beneficial in patients with neurogenic bladder dysfunction or in patients with functional or anatomical BOO. Neurourol. Urodynam. © 2006 Wiley‐Liss, Inc.

2004-11-01·Journal of Cardiovascular Pharmacology4区 · 医学

Influence of Endothelin Receptor Antagonism on Smooth Muscle Cell Proliferation After Chronic Renal Failure

4区 · 医学

Article

作者: Wolf, Sabine ; Brehm, Bernhard ; Risler, Teut ; Sauter, Gabriele

Uremic patients suffer from an accelerated development of atherosclerosis. In uremia the angiotensin-aldosterone-endothelin system is activated. It is not known, however, whether endothelin receptor antagonism inhibits atherosclerosis in uremia. An experimental model of mild renal insufficiency is subtotal nephrectomy in rats. The aim of this study was to assess the proliferative response of vascular smooth muscle cells from rats that have undergone subtotal nephrectomy and are treated with an endothelin-A or combined endothelin-A/endothelin-B receptor antagonist to the proatherogenic growth factors platelet-derived growth factor-BB and basic fibroblast growth factor. For 12 weeks 5/6-nephrectomized rats were treated with the endothelin-A receptor antagonist LU 302146 or the combined endothelin-A/endothelin-B receptor antagonist LU 302872 (10 mg/kg bodyweight)or received no medication (subtotal nephrectomy). Aortal smooth muscle cells were isolated and cultivated. After incubation with platelet-derived growth factor-BB (10(-13)-10(-9) mol/L for 5 days) or basic fibroblast growth factor (10(-14)-10(-10) mol/L for 7 days) proliferation was measured using bromodeoxyuridine enzyme-linked immunosorbent assay. Both growth factors increased proliferation in vascular smooth muscle cells from untreated subtotally nephrectomized rats (platelet-derived growth factor-BB10(-9) mol/L: 487%, basic fibroblast growth factor 10(-10) mol/L:175%). Treatment with the endothelin-A receptor antagonist resulted in a reduced proliferation (platelet-derived growth factor-BB: 137%, basic fibroblast growth factor: 109%). After treatment with the combined endothelin-A/endothelin-B receptor antagonist findings were similar (platelet-derived growth factor-BB: 123%,basic fibroblast growth factor: 110%). These data demonstrate that chronic endothelin-A and combined endothelin-A/endothelin-B receptor antagonism inhibits vascular smooth muscle cell proliferation in rats treated with subtotal nephrectomy. This indicates a regulatory influence of these drugs on gene transcription and supports the importance of early treatment to inhibit coronary artery disease in uremic patients.

2004-05-01·The Journal of Thoracic and Cardiovascular Surgery1区 · 医学

The endothelin 1a receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein–carotid artery interposition grafts

1区 · 医学

Article

作者: Smith, Frank C. T. ; Johnson, Jason L. ; Shukla, Nilima ; Dashwood, Michael R. ; Wan, Song ; Angelini, Gianni D. ; Jeremy, Jamie Y. ; Yim, Anthony P. C.

OBJECTIVELate saphenous vein graft failure after coronary artery bypass graft surgery is initiated by medial thickening and neointima formation, both of which are mediated by the proliferation of vascular smooth muscle cells. Because porcine vein grafts contain high levels of endothelin 1 receptor subtypes and endothelin 1 promotes the proliferation of vascular smooth muscle cells, the effect of administration of the endothelin 1(A) receptor antagonist BSF 302146 ([+]-[S]-2-[4,6-dimethyl-pyrimidin-2-yloxy]-3,3-diphenyl-butanoic acid) on porcine vein graft thickening was investigated.METHODSSaphenous vein-carotid artery interposition grafting was performed in 4 groups of large white pigs (30-35 kg, n = 10 for each group). BSF 302146 was administered orally (3, 10, and 30 mg x kg(-1) x d(-1)) for 4 weeks to one group of pigs, and placebo was administered to the other group (control animals). Pigs were then anesthetized, and the grafts were removed and fixed at 100 mm Hg with 4% paraformaldehyde. Histologic sections were prepared, and graft morphometry was carried out by using computer-aided planimetry.RESULTSIn vein grafts from animals treated with BSF 302146 compared with grafts from control animals (untreated), there were significant dose-dependent reductions in the increase in medial thickness and neointimal thickness, an increase in luminal area, and a decrease in proliferating cell nuclear antigen-positive cells in the medial-intimal area.CONCLUSIONSThe administration of BSF 302146 reduces graft thickening and promotes positive remodeling through an endothelin 1(A)-mediated effect on vascular smooth muscle cell replication. The administration of this endothelin 1(A) receptor antagonist might therefore be therapeutically effective in preventing late vein graft failure in patients undergoing coronary artery bypass grafting.

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适应症	最高研发状态	国家/地区	公司	日期
高血压	临床2期	-	AbbVie, Inc.	-
高血压	临床2期	德国	Abbott Laboratories	-
心脏衰竭	临床1期	德国	Abbott Laboratories	-
心脏衰竭	临床前	-	AbbVie, Inc.	-