Biomedical subjects

M Clozel

Publications and source records attributed to M Clozel.

At least 37 records · Page 2Linked to original sources

PubMed1997

Absence of ET(B)-mediated contraction in Piebald-lethal mice.

Activation of the endothelin (ET) ET(B) receptor can mediate opposite effects, endothelium-dependent vasodilation but also direct vasoconstriction. So far one gene encoding an ET(B) receptor has been identified and associated with endothelium-dependent relaxation. It has been suspected that the presence of another ET(B) gene could explain ET(B)-mediated contraction. The goal of the present study was to evaluate in Piebald-lethal (s[1]) mice, a naturally occurring mutant with deletion of the known ET(B) receptor gene, whether ET(B) receptor-mediated constriction is lost. Piebald-lethal (s[1]) mice, in contrast to control mice, completely lacked ET(B) specific ligand binding. The pressor effect of the ET(B) receptor selective agonist sarafotoxin S6c was completely absent. In vitro, contraction of stomach strips induced by sarafotoxin S6c was also abolished in Piebald-lethal (s[1]) mice. These results demonstrate the responsibility of the known ET(B) receptor gene in ET(B)-mediated constriction.

Animals↗

PubMed1997

Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm.

Endothelin (ET) receptor antagonists are of great potential clinical interest for the treatment pathological conditions associated with vasospasm, such as subarachnoid hemorrhage (SAH). We developed for parenteral use a compound of a class of trifunctionalized heteroarylsulfonamide pyrimidines specially designed for high water solubility. Ro 61-1790 [5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ETA receptor in the subnanomolar range. It has a approximately 1000-fold selectivity for the ETA vs. the ETB receptor as assessed on functional assays (e.g., ET-1-induced inositol-1,4, 5-triphosphate release or ET-1-induced intracellular calcium mobilization). Ro 61-1790 also had a high functional potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ETA receptors; pA2 = 9.5) or by sarafotoxin S6c on rat trachea (ETB receptors; pA2 = 6.4). In vivo, Ro 61-1790 inhibited the pressor effect of big ET-1 in pithed rats with an ID50 value of 0.05 mg/kg. Intravenous bolus of Ro 61-1790 induced a long-lasting antihypertensive effect in deoxycorticosterone acetate salt rats instrumented with telemetry. In a double-hemorrhage canine model of SAH, Ro 61-1790 both prevented and reversed cerebral vasospasm in a dose-dependent manner. In an established cerebral vasospasm, 3 mg/kg Ro 61-1790 i.v. was half as efficacious as intrabasilar papaverine. Ro 61-1790 (20 mg/kg/day) totally prevented the occurrence of vasospasm. In summary, these data demonstrate that Ro 61-1790 is a potent and selective ETA receptor antagonist suitable for parenteral use and potentially useful for preventing delayed ischemic deficit in patients with SAH.

Animals↗

PubMed1996

The role of ETB receptors in normotensive and hypertensive rats as revealed by the non-peptide selective ETB receptor antagonist Ro 46-8443.

We used Ro 46-8443, non-peptidic antagonist selective of endothelin ETB receptors, to study the role of ETB receptors in rat hypertension models. In normotensive rats, Ro 46-8443 decreased blood pressure, but in SHR and DOCA rats, it induced a pressor effect, due to blockade of ETB-mediated release of nitric oxide since L-NAME prevented it. In rats rendered hypertensive by chronic L-NAME, Ro 46-8443 did not induce a pressor but depressor effect. Thus, in DOCA rats and SHR, Ro 46-8443 reveals a predominant influence of endothelial 'vasorelaxant' ETB receptors, while in normotensive rats the prevailing role of ETB receptors seems to be in mediating a vasoconstrictor tone.

Animals↗

PubMed1996

In vitro characterisation of Ro 46-8443, the first non-peptide antagonist selective for the endothelin ETB receptor.

We describe here Ro 46-8443, the first non-peptide endothelin ETB receptor selective antagonist. It displays up to 2000-fold selectivity for ETB receptors both in terms of binding inhibitory potency and functional inhibition. The observed parallel rightward shift of concentration-response curves with different antagonist concentrations is consistent with a competitive binding mode. Since R0 46-8443 selectively inhibits ETB receptor mediated responses, it is a valuable tool for clarifying the role of ETB receptors in pathology.

Animals↗

PubMed1996

Respective role of humoral factors and blood pressure in aortic remodeling of DOCA hypertensive rats.

Hypertension results in increased thickness and stiffness of large artery walls. The goal of our study was to assess the respective roles of humoral factors such as Ang II, endothelin and blood pressure in these aortic modifications. For this purpose, uninephrectomized rats received DOCA and high salt diet, and when hypertension was installed, they were treated for 5 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg/day), an ACE inhibitor, enalapril (3 mg/kg/day), or a mixed ETA and ETB endothelin receptor antagonist, bosentan (100 mg/kg/day). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, aortic medial thickness and elastin as well as collagen were evaluated by quantitative morphometry. DOCA-salt hypertensive rats exhibited a marked increase in medial thickness associated with no change in absolute content in extracellular matrix. Elastin relative density decreased in DOCA rats. Enalapril had no effect on arterial pressure. Bosentan decreased slightly (by 12 mm Hg), but not significantly, blood pressure. None of these drugs had an effect on medial thickness suggesting that in DOCA hypertensive rats neither Ang II nor endothelin play a significant role in the remodeling of the aorta. In contrast, mibefradil almost normalized arterial pressure, prevented medial hypertrophy and increased elastin density. Further studies are required in order to assess if this effect is directly linked to the blood pressure decrease or to another mechanism related to the calcium antagonistic property of mibefradil.

Angiotensin II↗

PubMed1996

The endothelin antagonist bosentan: hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs.

In this study, we investigated the hemodynamic effects and receptor-blocking properties of the nonselective endothelin antagonist bosentan in pigs during normoxia and acute hypoxia. Hypoxic pulmonary hypertension was induced by decreasing the fraction of inhaled oxygen to 0.1. In a control group of pigs, hemodynamic parameters proved to be stable through 2 hours of hypoxia. Infusions of endothelin-1, endothelin-3, and sarafotoxin 6c into the pulmonary artery resulted in pulmonary and systemic vasoconstriction during normoxia, whereas endothelin administration during hypoxic pulmonary hypertension resulted in pulmonary vasodilation. After administration of bosentan, the vasopressor effect of endothelin-1 during normoxia was significantly attenuated and the pulmonary vasodilatory effect of endothelin-1 during hypoxia was reduced. Furthermore, the development of hypoxic pulmonary hypertension was significantly reduced by bosentan. In contrast, bosentan did not influence the pulmonary vasopressor response to the thromboxane mimic U-46619. We therefore conclude that vasopressor endothelin receptors seem to be activated by endogenous endothelin released during hypoxia, leading to an increase in the pulmonary vascular tone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1996

Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries.

Both endothelin-A (ETA) and endothelin-B (ETB) receptors are known to be present in human coronary arteries. However, their absolute and relative amounts, functional roles, and the influence of pathology are uncertain. The goal of the present study was to characterize endothelin receptors mediating constriction in human coronary arteries and to assess the influence of cardiomyopathy (CMP) and coronary artery disease (CAD) on ET receptors in human tissue. For comparison, porcine coronary arteries were evaluated in parallel. Competition binding experiments using [125I]ET-1 and different selective and nonselective ETA- and ETB-receptor agonists or antagonists revealed similar relative densities (relative Bmax) of ETA and ETB receptors in coronary arteries from human cardiomyopathic hearts (83% ETA and 17% ETB; n = 5) and porcine hearts (78% ETA and 22% ETB; n = 5). In marked contrast, the relative Bmax of ETB receptors were significantly higher in coronary arteries from human atherosclerotic hearts (51% ETA and 49% ETB; n = 3). Total receptor density (Bmax; fmol/mg protein) was highest in porcine (385 +/- 29) arteries, followed by human CAD (253 +/- 41) and CMP (174 +/- 20) coronary arteries. The relative and absolute Bmax values for ETA and ETB receptors in coronary arteries from a donor heart were similar to those obtained in CMP hearts. There were no significant differences in affinity constants (KD) values for ET-1, ET-3, Sarafotoxin S6c (SRTX S6c), BQ-123, and bosentan (Ro 47-0203) between tissues. In human coronary arteries from CMP hearts, ET-induced constriction seemed to be solely mediated via ETA receptors. In contrast, in porcine coronary arteries 20% of the maximal effect mediated by ET-1 could be attributed to ETB receptors, in agreement with the binding data. The functional role of ETB receptors in CAD tissue could not be evaluated because of the occurrence of spontaneous phasic contractions. We conclude that ETB receptors are up-regulated in human atherosclerotic coronary arteries. Further studies are needed to determine the pathophysiological importance of these receptors.

Acetylcholine↗

PubMed1996

Telemetry monitoring of pulmonary arterial pressure in freely moving rats.

Several rat models of pulmonary hypertension have been developed. However, up until now it has been difficult to monitor pulmonary arterial pressure for long periods of time. The goal of the present study was to develop a telemetry system allowing chronic monitoring of pulmonary arterial pressure in freely moving rats. For this purpose, while animals were under anesthesia, a sensing catheter was implanted into the pulmonary arterial trunk through the right ventricle. This catheter was connected to an emitter implanted in the abdomen. Validation of the system was performed in three steps. First, acutely, we controlled that the pressure signal transmitted by the telemetry system was accurate and corresponded to a signal obtained with a high-fidelity Millar catheter. Second, we evaluated the chronic consequences of implantation of the system. Third, we used the system to monitor pulmonary arterial pressure in a model of monocrotaline-induced hypertension in which the effects of bosentan, an endothelin-receptor antagonist, were evaluated. The telemetry system was reliable and did not lead to damage of the right ventricle and/or to chronic pulmonary embolism. After a recovery period of 8-10 days, mean pulmonary arterial pressure was stable. With the use of this telemetry system, it was possible to follow the increase of pulmonary arterial pressure induced by monocrotaline. In this model, bosentan decreased mean pulmonary arterial pressure by 13% (P = 0.07), suggesting a role of endothelin in this model of pulmonary hypertension. We conclude that it is possible to use this telemetry system to monitor pulmonary arterial pressure in freely moving conscious rats.

Animals↗

PubMed1996

Nimodipine does not increase cerebral blood flow during subarachnoid hemorrhage in the rat.

The purpose of this study was to determine the effects of nimodipine, a calcium antagonist, on regional cerebral blood flow (CBF) in experimental subarachnoid hemorrhage (SAH) rats. Regional CBF was measured by the radioactive microspheres method. Experimental SAH was induced by a single injection of autologous arterial blood (0.3 ml) into the cisterna magna in anesthetized rats. Rats subjected to SAH showed an immediate and marked reduction of CBF in all brain regions throughout the experimental period. The infusion of nimodipine (1 microgram/kg/min) was started 30 min before the induction of the experimental SAH and continued during the experiments. Nimodipine did not prevent the reduction of regional CBF after SAH. It is concluded that nimodipine only increases regional CBF in normal animals, but dose not affect the reduction of CBF after experimental SAH.

Animals↗

PubMed1996

Endothelin antagonism in end-organ damage of spontaneously hypertensive rats. Comparison with angiotensin-converting enzyme inhibition and calcium antagonism.

High blood pressure results in cardiac hypertrophy and fibrosis, increased thickness and stiffness of large artery walls, and decreased renal function. The objective of our study was to assess the role of endothelin, angiotensin II, and high blood pressure in the end-organ damage observed in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 10 weeks with either a mixed endothelin-A and endothelin-B receptor antagonist, bosentan (100 mg/kg per day), an angiotensin-converting enzyme inhibitor, enalapril (10 mg/kg per day), or a long-acting calcium antagonist, mibefradil (20 mg/kg per day). A group of SHR was left untreated, and a group of normotensive Wistar rats was used as control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and fibrosis, aortic medial thickness, and extracellular matrix content were evaluated by quantitative morphometry. Proteinuria and urea and creatinine clearances were measured, and renal histopathology was assessed. SHR exhibited cardiac hypertrophy, perivascular fibrosis, and decreased maximal coronary blood flow. Aortic medial thickness was increased, whereas elastin density was decreased. Finally, SHR showed decreased urinary excretion and decreased urea and creatinine clearances. No renal histological lesions were observed. Although bosentan did not affect blood pressure, it normalized renal function and slightly decreased left ventricular hypertrophy and fibrosis. Enalapril and mibefradil were both effective in significantly decreasing blood pressure, left ventricular hypertrophy, and aortic medial thickness and improving coronary blood flow, but in contrast to bosentan, they did not improve creatinine clearance. We conclude that in SHR, high blood pressure plays a major role in end-organ damage and that endothelin may partly mediate renal dysfunction and cardiac remodeling independently of a direct hemodynamic effect.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Respective role of humoral factors and blood pressure in cardiac remodeling of DOCA hypertensive rats.

OBJECTIVES: Recent studies have shown that beside elevated arterial blood pressure, humoral factors such as angiotensin II, aldosterone, endothelin or bradykinin might play a role in the cardiac hypertrophy and fibrosis secondary to hypertension. In addition, it seems that perivascular fibrosis and interstitial fibrosis are controlled by independent mechanisms. Therefore, the goal of our study was to evaluate the respective role of the increased arterial pressure and of humoral factors on cardiac remodeling in an experimental hypertension model. METHODS: Uninephrectomized rats received DOCA, a high salt diet, and when hypertension was installed, they were treated for 6 weeks with either a long-acting calcium antagonist, mibefradil (30 mg/kg day-1), an ACE inhibitor, enalapril (3 mg/kg day-1), or a mixed ETA-ETB endothelin receptor antagonist, bosentan (100 mg/kg day-1). A group of hypertensive rats was left untreated and a sham-operated group of normotensive rats was used for control. At the end of treatment, maximal coronary blood flow was measured in isolated perfused hearts. Cardiac hypertrophy and interstitial as well as perivascular fibrosis were evaluated by quantitative morphometry. RESULTS: DOCA-salt hypertensive rats exhibited a marked cardiac hypertrophy associated with a decrease of maximal coronary blood flow and interstitial and perivascular fibrosis. The calcium antagonist nearly normalized arterial pressure and suppressed all these changes. Enalapril had no effect on arterial pressure and perivascular fibrosis but decreased subendocardial fibrosis. Bosentan had a very small effect on arterial pressure but decreased cardiac hypertrophy and both perivascular and subendocardial fibrosis. CONCLUSIONS: We conclude that in DOCA salt hypertension, humoral factors such as endothelin may play a role beside high blood pressure in cardiac remodeling. In addition, the different components of this remodeling (decrease of vascular reserve, cardiac hypertrophy and cardiac fibrosis) are controlled independently.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Role of endothelins for renin regulation.

Endothelins 1, 2, and 3 did not affect basal renin secretion, but selectively inhibited to a similar extent both cAMP-stimulated renin secretion and renin gene expression in isolated renal juxtaglomerular cells. In isolated perfused rat kidneys and after cAMP-stimulated renin secretion using isoproterenol, endothelins inhibited basal renin secretion at a perfusion pressure of 80 mm Hg. Endothelin's main action is mediated via the endothelin ETB receptor. It involves activation of phospholipase C, intracellular calcium mobilization in juxtaglomerular cells that is dependent on extracellular calcium and associated with prominent calcium-activated chloride currents, and subsequent processes. In normal rats and in rats with unilateral renal artery clips, a nonselective inhibitor of endothelin receptors, Ro 47-0203, did not significantly change renin secretion and renal renin gene expression, despite complete abolition of the vasoconstrictive and renin inhibitory action of exogenous endothelins by this drug in isolated perfused rat kidneys. In spite of a marked renin inhibitory efficacy of exogenous endothelins in vitro (isolated renal juxtaglomerular cells, isolated perfused rat kidney), endogenous endothelins play no relevant regulatory role in renin secretion and renin gene expression in normal and hypoperfused rat kidneys in vivo. However, endothelins may be of physiological relevance for the development of hypertension upon renal artery stenosis.

Animals↗

PubMed1995

Separable binding sites for the natural agonist endothelin-1 and the non-peptide antagonist bosentan on human endothelin-A receptors.

A three-dimensional model for the transmembrane domains of human endothelin-A receptor was built using structural information from bacteriorhodopsin and sequence alignment to other guanine-nucleotide-binding regulatory(G) protein-coupled receptors. Based on this model, 18 amino acids located at the inside of the receptor were mutated and analyzed for binding of the natural ligand endothelin-1 and bosentan, a recently described potent orally active endothelin antagonist [Clozel, M., Breu, V., Gray, G., Kalina, B., Löffler, B.-M., Burri, K., Cassal, J.-M., Hirth, G., Müller, M., Neidhart, W. & Ramuz, H. (1994) Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist, J. Pharmacol. Exp. Ther. 270, 228-235]. Mutation of Gly97, Lys140, Lys159, Gln165 and Phe315, located in transmembrane region 1, 2, 3, 3, and 6, respectively, caused reduced specific binding of 125I-labelled endothelin-1, despite an expression level similar to wild-type endothelin-A receptor. Mutation of Tyr263, Arg326 and Asp351 preserved endothelin-1 binding but caused reduced binding of bosentan. These amino acids, located on transmembrane regions 5, 6 and 7, respectively, are conserved among endothelin-A and endothelin-B receptors but not in other G-protein-coupled receptors. These observations demonstrate a dissociation of the binding site for the peptidic natural agonist endothelin-1 and the synthetic non-peptide antagonist bosentan. They provide the molecular basis for bosentan being a specific antagonist for both, endothelin-A as well as endothelin-B receptors and may in combination with studies on structure/activity relationship support the design of novel and more potent endothelin receptor antagonists.

Amino Acid Sequence↗

PubMed1995

In vivo evidence of an endothelin-induced vasopressor tone after inhibition of nitric oxide synthesis in rats.

BACKGROUND: Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin. Thus, inhibition of NO synthesis might unmask a vasopressor response to endothelin. To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). METHODS AND RESULTS: Anesthetized rats received increasing doses of L-NAME (0.1 to 3 mg.kg-1) in the absence or the presence of bosentan (3 mg.kg-1 IV 15 minutes before L-NAME). Bosentan itself did not affect blood pressure. L-NAME induced a dose-dependent increase in mean arterial pressure (percent increase from baseline after 3 mg.kg-1, 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; P < .05) or by the selective ETA antagonist BQ-123 (3 mg.kg-1: controls, 25 +/- 4%; BQ-123, 14 +/- 5%; P < .01). In contrast, bosentan did not affect the pressor response to phenylephrine (1 to 100 micrograms.kg-1). The response to L-NAME (3 mg.kg-1) was also reduced by bosentan in ganglion-blocked (chlorisondamine 2.5 mg.kg-1: controls, 89 +/- 10%; bosentan, 45 +/- 7%) or pithed rats (controls, 165 +/- 9%; bosentan, 85 +/- 12%; P < .01). Bosentan also inhibited the pressor response to another inhibitor of NO synthesis, NG-nitro L-arginine (3 mg.kg-1) in normal (controls, 24 +/- 5%; bosentan, 10 +/- 3%; P < .01) or ganglion-blocked (controls, 86 +/- 13%; bosentan, 25 +/- 8%; P < .01) rats. Finally, L-NAME induced a modest increase in plasma levels of endothelin-1 (controls, 26.8 +/- 4.1 pg.mL-1; L-NAME, 38.5 +/- 3.3 pg.mL-1; P < .05). CONCLUSIONS: These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.

Animals↗

PubMed1995

Comparative evaluation of acute cerebral vasospasm by the microsphere and the angiography techniques.

Experimental subarachnoid haemorrhage (SAH) induces an acute transient cerebral vasospasm. The goal of this study was to compare angiography with iterative measurements of regional cerebral blood flow (rCBF) by the microsphere technique for tracking acute cerebral vasospasm after SAH. Cerebral vasospasm was induced in anaesthetised rabbits by injecting 1 ml of fresh blood in the cisterna magna. In a first experiment, the diameter of the basilar artery was measured by repeated angiograms over 60 min. In a second experiment, rCBF was measured over 60 min by the radioactive microspheres method without and with bilateral ligation of the carotid artery. Without carotid ligation, despite a profound transient vasospasm of the basilar artery, rCBF was unchanged in the cerebellum and cerebrum and was not statistically decreased in the brain stem. However, with bilateral carotid ligation, rCBF dramatically decreased at 5 and 15 min after haemorrhage. At 30 min, despite a persistent 50% decrease in the basilar cross-sectional area, rCBF was no longer different from the control group. Thus in a model of acute vasospasm of the basilar artery, rCBF evaluation by the microsphere technique parallels the cerebral vasospasm evaluated by angiography only when both carotid arteries are ligated.

Anesthesia↗

PubMed1995

Role of endogenous endothelin in normal hemodynamic status of anesthetized dogs.

Endothelin (ET) is a potent vasoconstrictor that may be involved in a number of cardiovascular disorders, although its role in normal hemodynamics remains unclear. Twenty-two anesthetized open-chest dogs were instrumented for measurement of systemic and pulmonary hemodynamics, cardiac output, coronary blood flow, and cardiac contractility. Big ET induced peripheral and coronary vasoconstriction, which occurred before significant elevations in plasma ET and which was nearly completely blocked by bosentan, a new nonpeptidic mixed (ETA and ETB) ET receptor antagonist. Bosentan also prevented the peripheral dilatation caused by the specific ETB receptor agonist, sarafotoxin S6c, but did not prevent the peripheral vasoconstriction induced by angiotensin II. Bosentan alone had no significant hemodynamic effect in the normal anesthetized dog, although it did induce a reactive increase in the plasma level of ET-1 and ET-3. This study demonstrates that, despite blocking both ETA and ETB receptors, bosentan alone had no hemodynamic effect, suggesting that ET does not play a major role in the normal hemodynamic status of anesthetized dogs.

Analysis of Variance↗

PubMed1995

Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats.

The aim of this study was to investigate the potential role of endothelin (ET) in the development of chronic hypoxic pulmonary hypertension. Pulmonary vascular reactivity to ET-1 was first examined in isolated perfused lungs from normoxic and chronically hypoxic rats in the presence of bosentan, a new nonpeptide mixed antagonist of ETA and ETB receptors. The effect of chronic treatment with bosentan was then examined in rats that were exposed to chronic hypoxia and developed pulmonary hypertension. In lungs from normoxic rats, bosentan (10(-5) M) abolished the vasodilator responses to ET-1 (10(-10) M) or to the ETB-selective agonist IRL-1620 (10(-10) M) and attenuated the vasoconstrictor responses to 10(-9) M ET-1 (from 8.7 +/- 0.7 to 1.8 +/- 0.3 mmHg, P < 0.01) or 10(-9) M IRL-1620 (from 1.5 +/- 0.4 to 0.4 +/- 0.1 mmHg, P < 0.05). In lungs from chronically hypoxic rats, the pressor response to 3 x 10(-10) M ET-1 was abolished by bosentan and partially reduced by the selective ETA antagonist BQ-123. In conscious rats previously exposed to hypoxia for 15 days, pretreatment with bosentan (100 mg.kg-1.day-1 by gavage) for 3 days attenuated the increase in systemic arterial pressures and the concomitant decrease of cardiac output in response to an intravenous bolus of ET-1 (3 x 10(-10) M). In rats exposed to hypoxia for 15 days and simultaneously treated with bosentan, pulmonary arterial pressure was lower (P < 0.05) and right ventricular hypertrophy was less severe (P < 0.01) than in control hypoxic rats treated with vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Role of endogenous endothelins in the renin system of normal and two-kidney, one clip rats.

This study aimed to investigate the relevance of endogenous endothelins in the control of renin secretion and renin gene expression under basal conditions and stimulated conditions achieved with unilateral renal artery stenosis. To this end, we studied the effects of the orally active endothelin antagonist Ro 47-0203 (100 mg/kg per day) for 2 days on plasma renin activity and renal renin mRNA levels in normal rats and rats with unilateral renal artery clips (0.2 mm). Treatment with Ro 47-0203 did not change basal arterial pressure but significantly attenuated the rise of blood pressure in response to renal artery clipping. Although Ro 47-0203 tended to increase basal plasma renin activity, this effect was not significant. Basal renin mRNA levels of kidneys were also not changed by the drug. Unilateral renal artery clipping increased plasma renin activity from 12 to 34 ng angiotensin I/mL per hour, increased renin mRNA levels to 328% of controls in the clipped kidneys, and decreased renin mRNA levels to 23% of controls in the contralateral intact kidneys. These changes were not influenced by Ro 47-0203. In isolated perfused rat kidneys, Ro 47-0203 (10 mumol/L) also had no effect on basal renin secretion or vascular resistance, but it substantially attenuated the decrease of renin secretion and renal flow in response to administration of exogenous endothelin. Taken together, these findings suggest that endogenous endothelins play no relevant role in the control of renin secretion and of renin gene expression in normal and hypoperfused rat kidneys.

Animals↗