Biomedical subjects

M Clozel

Publications and source records attributed to M Clozel.

At least 55 records · Page 3Linked to original sources

PubMed1995

The role of endothelin in experimental cerebral vasospasm.

Endothelin (ET) may play a role in vasospasm after subarachnoid hemorrhage (SAH). The aim of our study was to test whether the systemic administration of bosentan, a nonpeptidic ET(A) and ETB receptor antagonist, could reverse vasospasm without inducing hypotension. In rabbits (single-hemorrhage model) and in dogs (double-hemorrhage model), SAH was induced; after vasospasm was established, the animals received intravenously either saline or a 30 mg/kg bolus of bosentan. The cross-sectional area of the basilar artery was analyzed by quantitative angiography. In rabbits (n = 13), bosentan reversed basilar vasospasm to the same extent as did an intravertebral injection of sodium nitroprusside. In dogs (n = 10), bosentan reversed only 52 +/- 10% of the vasospasm reversible by papaverine. Bosentan did not alter the heart rate or the arterial blood pressure in either the rabbits or the dogs. In the cerebrospinal fluid, SAH increased endothelin-1 (ET1) and big ET1 by 6 and 3.8 times, respectively; in the basilar artery, SAH increased ET1 concentration, big ET1 concentration, and ET-converting enzyme activity by 1.3, 2, and 2.7 times, respectively. In addition, a local involvement of ET was also suggested by the relaxing effect of bosentan on basilar artery rings from rabbits with SAH and not from control rabbits. Receptor binding studies performed on dog basilar arteries revealed a shift in the phenotype expression of ET receptors from the A to the B type after SAH. We conclude that ET plays a major role in SAH and that systemic ET blockade might selectively dilate spastic arteries.

Animals↗

PubMed1995

The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm.

Using the canine chronic cerebral vasospasm model, we studied the effects of a potent new nonpeptidic endothelin-1 (ET1) receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4 - yl]-benzenesulfonamide). Endothelin (ET) receptors are composed of the ETA receptors and the ETB receptors; ET1 acts on both of these receptors. Although it has been previously thought that the ETA receptor mediates vasoconstriction, whereas the ETB receptor mediates vasodilation, recent evidence suggests that ETB receptor also contributes to vasoconstriction. Because bosentan is a mixed antagonist that acts on both receptors, its use might indicate whether or not ET is involved in the pathogenesis of cerebral vasospasm. In this study, beagle dogs received a double injection of autologous arterial blood into the cisterna magna at 2-day intervals (i.e., on Days 0 and 2). The diameter of the basilar artery (BA) was angiographically examined up to Day 7. A total of 24 dogs were randomly allocated to either the treatment group or the no-treatment group. Eight dogs were treated with 10 mg/kg bosentan by a one-dose injection into a central venous catheter. Bosentan was given twice a day starting immediately after the first subarachnoid hemorrhage for 6 days until Day 5. Sixteen dogs served as controls, with untreated subarachnoid hemorrhage. After the injection of bosetan, blood pressure decreased by about 25 mm Hg for a few minutes and then returned to normal. In the dogs treated with bosentan, the BA spasm on Day 7 was significantly ameliorated compared with the BA spasm in the untreated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Role of endothelin in acute renal failure due to rhabdomyolysis in rats.

Rhabdomyolysis and other causes of massive myoglobin release are often complicated by an acute ischemic renal failure. We tested the hypothesis that endothelin-1, the most potent renal vasoconstrictor known, plays a role in the renal toxicity of myoglobin. For this purpose, we induced rhabdomyolysis (8 ml/kg i.m. of a 50% glycerol solution) in rats pretreated or not pretreated with bosentan, a novel potent nonpeptide endothelin receptor antagonist. Glycerol decreased renal function dramatically, increased proteinuria and induced a massive tubular necrosis. This effect was associated with a 22% increase in plasma endothelin concentration. Bosentan prevented the decrease in creatinine clearance (1.12 +/- 0.07 ml/min vs. 0.83 +/- 0.05 ml/min, P < .01), the increase in proteinuria (19.9 mg/24 hr vs. 31.8 mg/24 hr, P < .001) and the tubular necrosis induced by glycerol (as assessed by histopathological evaluation), without affecting myoglobinuria. Involvement of endothelin was further suggested by the observation that myoglobin could markedly increase endothelin-1 release by rat mesangial cells in culture. We conclude that endothelin is, at least in part, responsible for the massive tubular necrosis observed in myoglobinuric nephropathy.

Acute Kidney Injury↗

PubMed1995

[Demonstration of a vasopressor role of endogenous endothelin after inhibition of nitric oxide synthesis in rats].

Although it is clear that vascular endothelial cells synthesize and release endothelin (ET), the contribution of this vasconstrictor peptide to the regulation of vascular tone appears limited in normal conditions. One possibility to explain this moderate effect is that continuous production of nitric oxide (NO) may permanently inhibit the release and the vasoconstrictor effects of ET. In these conditions, inhibition of NO synthesis might unmask a vasopressor response to ET. Thus, we tested whether bosentan (3 mg/kg i.v.), a non-peptide antagonist of ETA and ETB receptors, or BQ-123 (3 mg/kg), an antagonist of ETA receptors, affected the hypertensive response induced by the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 3 mg/kg) or NG-nitro L-arginine (3 mg/kg) in anesthetized, normotensive rats. Bosentan or BQ-123 did not affect blood pressure. L-NAME significantly increased mean arterial pressure (% increase from baseline: 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; p < 0.05) or by BQ-123 (14 +/- 5%; p < 0.01). In contrast, bosentan did not affect the pressor response to phenylephrine. The response to L-NAME (3 mg/kg) was also reduced by bosentan in ganglion-blocked (chlorisondamine: 2.5 mg/kg; controls 89 +/- 10; bosentan: 45 +/- 7%) or pithed rats (controls: 165 +/- 9; bosentan 85 +/- 12%; p < 0.01). Bosentan also inhibited the pressor response to NG-nitro L-arginine (3 mg/kg-1) in normal (controls 24 +/- 5, bosentan 10 +/- 3%; p < 0.01) or ganglion-blocked rats (controls 86 +/- 13; bosentan 25 +/- 8; p < 0.01). Finally, L-NAME induced a modest increase in plasma levels of ET-1 (controls: 26.8 +/- 4.1; L-NAME: 38.5 +/- 3.3 pg/ml; p < 0.05). Thus, acute inhibition of NO synthesis unmasks a tonic vasopressor influence of ET.

Animals↗

PubMed1995

Endothelin receptors that modulate contraction of the rat fundus.

The present study aimed to characterize endothelin (ET) receptors mediating the effects of ET-1 in the rat fundic strip. Functional studies demonstrated that ET-1 and the ETB receptor-selective agonist sarafotoxin S6c elicit contraction of the rat fundic strip via high-affinity ETB receptors. Contraction was potentiated by the ETA receptor antagonist BQ 123 (10 microM) and the mixed antagonist bosentan (10 microM), suggesting that ET-1 also activates ETA and ETB receptors that inhibit contraction. This ET-1-mediated inhibition of contraction was blocked by an inhibitor of Ca(2+)-activated K+ channels, apamin (50 microM). Competitive binding studies revealed the presence of one BQ 123-sensitive and two BQ 123-insensitive binding sites that showed different affinity for ET-3 in the pM and nM range, respectively. These observations demonstrate the presence of multiple receptors in the rat fundus and suggest that smooth muscle contraction is counteracted by activation of Ca(2+)-activated K+ channels by ET-1.

Animals↗

PubMed1995

Role of endothelin in spontaneous phasic contraction of human coronary arteries.

Isolated human coronary arteries are known to develop spontaneous phasic contractions (SPCs). The goal of the present study was to assess the role of endothelin (ET) in these contractions. Endothelium-denuded rings from left anterior descending (LAD) coronary arteries of patients with coronary artery disease (CAD; n = 3) undergoing cardiac transplantation developed SPCs within 1-2 h. The contractions were abolished by the ETA receptor antagonist BQ-123 or the mixed ET receptor antagonist bosentan (1 and 3 microM), whereas the contractions persisted for several hours in control rings. Exogenous ET-1 (10 pM) increased the amplitude of SPCs and initiated SPCs in rings that did not exhibit SPCs. Higher concentrations of ET-1 (> or = 1 nM) were able to re-induce SPC in rings in which SPCs had been abolished by BQ-123 or bosentan. These results suggest that ET plays an important role in spontaneous phasic contractions of isolated human coronary artery rings.

Coronary Vessels↗

PubMed1995

Are there different ETB receptors mediating constriction and relaxation?

Because certain antagonists of endothelin (ET) ETB receptors (such as the mixed ETA+ETB antagonist PD 142893 or the selective ETB receptor antagonist BQ-788) were shown to antagonize the ETB-mediated dilatation to ET-1 but not the ETB-mediated constriction to ET-1, the existence of two subtypes of to ET-1, the existence of two subtypes of ETB receptors was suggested. The goal of the present study was to further explore this absence of functional antagonism of ETB-mediated constriction by so-called ETB receptor antagonists. In rat tracheal rings denuded of epithelium, Ro 46-8443, a selective ETB receptor antagonist, did not shift the concentration-response curve of ET-1 but antagonized sarafotoxin S6c-induced contractions. However, the ET-1-mediated contractions could be attributed to ETB receptor activation, because BQ-123 had no inhibitory effect except at high doses of ET-1. Preincubation of tracheal rings with BQ-123 (10(-5) M) to block ETA receptors revealed an antagonist effect of Ro 46-8443 on contractions induced by ET-1. By analogy with these pharmacologic experiments, desensitization of ETB receptors by preincubation with sarafotoxin S6c did not modify contractile responses to ET-1 except when the tracheal rings were exposed to BQ-123. We conclude that on rat tracheal rings, ET-1 and sarafotoxin S6c activate a common ETB receptor. However, blockade of ETB receptors is not sufficient for inhibition of ET-1-mediated responses because of cross-talk between receptors that allows ETA to compensate for a blockade of ETB receptors. This study suggests that the endothelial ETB receptor mediating dilatation and the smooth muscle cell ETB receptor mediating constriction may not represent two different subtypes.

Animals↗

PubMed1994

Endothelin plays a role in the maintenance of blood pressure in normotensive guinea pigs.

The objective of the present study was to evaluate if endothelin plays a role in the maintenance of arterial blood pressure in normotensive guinea pigs. For this purpose, the effects of a new mixed (ETA + ETB) endothelin receptor antagonist, Ro 47-0203 (bosentan), were evaluated in vitro on aortic rings and in anesthetized and conscious guinea pigs. In vitro, bosentan was a potent (pA2 = 7.5) and competitive endothelin receptor antagonist as shown by the parallel rightward shift of the concentration-response curve for endothelin-1 on guinea pig aortic rings in presence of increasing concentrations of bosentan. In vivo, bosentan significantly decreased arterial blood pressure of both anesthetized and conscious guinea pigs. This effect was similar to the effect of BQ-123, a selective ETA receptor antagonist. No additional effect was observed when bosentan was given on top of BQ-123. Neither inhibition of the renin angiotensin system with remikiren, cyclooxygenase inhibition with indomethacin, bradykinin antagonism with Hoe 140, ganglionic blockade with chlorisondamine, parasympathetic inhibition with atropine nor nitric oxide synthase blockade with L-NAME altered the effect of bosentan. In conclusion, the present results show that endothelin contributes to the maintenance of arterial blood pressure in normal normotensive guinea pigs most likely through stimulation of ETA receptors.

Animals↗

PubMed1994

Role of endothelin during reperfusion after ischemia in isolated perfused rat heart.

We assessed the role of endogenous endothelin (ET) in reperfusion injury using a novel nonpeptidic ET antagonist of ETA and ETB receptors: bosentan (Ro 47-0203). In preliminary experiments in nonischemic rat hearts, we confirmed that bosentan 10(-5) M could block the changes in coronary flow (CF) and release of prostacyclin induced by ET-1 and the ETB-selective agonist sarafotoxin S6c (SRTX S6c). Thereafter, we induced global ischemia in paced hearts by closing the perfusion line for 20 min; this was followed by reperfusion. In one group of rats, bosentan (10(-5) M) was added to the perfusion medium before ischemia. In preischemic conditions, bosentan slightly increased CF by 14% (p = 0.094) in nonpaced hearts and by 35% (p = 0.001) in paced hearts, but did not influence cardiac contractility. Global ischemia produced severe ischemic damage, as shown by electromechanical dissociation (EMD) and decreased cardiac contractility. Bosentan did not influence recovery of cardiac function and did not ameliorate postischemic hemodynamic variables as compared with those of the control group. We conclude that endogenous ET does not play a major role in induction of reperfusion injury in isolated perfused rat heart.

Animals↗

PubMed1994

Characterization of receptors mediating vascular responses to endothelin-1 in the conscious rat.

1. The present study has determined the receptors mediating the vascular responses (pressor and depressor actions and vascular permeability effect) to endothelin-1 (ET-1) in the conscious rat by using the novel non-peptide ETA/ETB receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2 hydroxyethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine- 4-yl]benzene-sulphonamide), the ETA receptor-selective antagonist, FR 139317 and the ETB receptor-selective peptide agonist, IRL 1620. 2. Bolus injection of ET-1 (1 nmol kg-1, i.v.) resulted in a prolonged pressor effect (maximum increase in mean arterial blood pressure (MABP) was 47 +/- 3 mmHg, n = 6) preceded by a transient depressor response (maximum decrease in MABP was 17 +/- 1 mmHg). Both these responses were inhibited by bosentan (1-20 mg kg-1, i.v. bolus) in a dose-dependent manner. The maximum inhibition of ET-induced depressor and pressor responses did not exceed 53 and 87%, respectively. FR 139317 (2.5 mg kg-1, i.v.) attenuated the pressor response to ET-1 by 75% without affecting the depressor response. Furthermore, FR 139317, but not bosentan, prolonged the depressor action of ET-1. Corresponding to changes in blood pressure, a small transient tachycardia (delta heart rate 15 +/- 5 beats min-1) followed by a sustained bradycardia (delta heart rate -48 +/- 10 beats min-1, n = 6) was observed following injection of 1 nmol kg-1 ET-1. FR 139317 and bosentan (10 mg kg-1) inhibited ET-1-induced bradycardia by 79% and 71%, respectively.ET-l-induced tachycardia was significantly attenuated by bosentan,but not FR 139317.3. The ETB receptor agonist, IRL 1620 (0.1-2 micro molkg-1, i.v.) produced biphasic dose-dependent changes in MABP with an initial transient fall followed by a prolonged pressor action. The maximum decrease and increase in MABP were 11 +/- 2 and 19 +/- 3 mmHg, respectively (n = 5). These changes in MABP were accompanied by a transient tachycardia (Delta heart rate 9+/- 3 beats min-1) and prolonged bradycardia (Delta heart rate -17+/-11 beats min-1), respectively. Pretreatment of the animals with FR139317 (2.5 mg kg-1, i.v.) did not affect IRL 1620 (1 nmol kg-1)-induced changes in MABP and heart rate, whereas both the depressor and pressor actions of IRL 1620 and the accompanying tachycardia and bradycardia were almost completely inhibited by bosentan (10mgkg-1).4. ET-1 (1 nmol kg-1) enhanced albumin extravasation in the upper and lower bronchi, spleen, kidney,stomach and duodenum (up to 246%) as measured by the extravasation of Evans blue dye. FR 139317(2.5mgkg-1) completely inhibited ET-l-induced protein extravasation in the stomach and duodenum,whereas 40-75% inhibition was observed in the other vascular beds studied. The permeability effect of ET-l was almost completely inhibited by bosentan (10mgkg-1) in all vascular beds studied.5. IRL 1620 (0.4 or 1 nmol kg-1, i.v.) enhanced albumin extravasation (up to 219%) in the upper and lower bronchi, spleen and kidney in a dose-dependent manner. Unlike ET-1, IRL 1620 failed to increase albumin extravasation in the stomach and duodenum.6. The present study demonstrates in the conscious rat that ETA and ETB receptors are responsible for mediating the majority of the pressor response to ET-l and suggest that a small component of the ET-l pressor response might be mediated via a non-ETA, non-ETB receptor, whereas ETB and perhaps a non-ETA, non-ETB receptor may mediate the depressor action of ET-1. Furthermore, the ET-1 induced albumin extravasation is mediated solely via ETA receptors in the stomach and duodenum, whereas both ETA and ETB receptors are involved in the permeability effect of ET-l in the bronchial, splenic and renal vascular beds.

Animals↗

PubMed1994

Characterization of endothelin receptors mediating contraction of rabbit saphenous vein.

The goal of this study was to characterize endothelin (ET) receptors mediating contraction of the rabbit saphenous vein. For this purpose, binding and functional studies were performed. Two receptor subtypes mediated contraction in response to ET-1. The first, responsible for 80-90% of maximal contraction, was stimulated with equal potency by ET-1, ET-3, and sarafotoxin S6c. The second, responsible for the remaining contraction, was stimulated more potently by ET-1 than by ET-3 and not by sarafotoxin S6c. The specific ETA receptor antagonist BQ-123 and the inhibitor of protein kinase C (PKC) Ro 31-8220 inhibited ET-1 contraction via the second but not the first receptor. In plasma membranes 125I-labeled ET-1 bound predominantly to a site with characteristics of ETA receptor, whereas 125I-ET-3 bound to two sites with characteristics of ETB receptor, one of high and one of low affinity. Comparison of binding affinity constants and 50% effective concentrations shows that the high-affinity ETB receptor corresponds to the receptor mediating the major part of contraction independently of PKC activation and ETA to the receptor mediating the minor part of contraction via a PKC-dependent mechanism.

Animals↗

PubMed1994

Increased vascular responsiveness to norepinephrine in rats with heart failure is endothelium dependent. Dissociation of basal and stimulated nitric oxide release.

BACKGROUND: Endothelial dysfunction and abnormal vascular responsiveness to vasoconstrictors may play an important role in chronic heart failure (CHF). The purpose of our study was to (1) evaluate whether the vascular response to norepinephrine is abnormal in a rat model of heart failure; (2) investigate the role of alpha 1- and alpha 2-adrenergic receptors; and (3) assess the contribution of the endothelium, and specifically endothelium-derived nitric oxide, to this response. METHODS AND RESULTS: Concentration-response curves of rat thoracic aortic rings were studied in isolated organ baths at 1 week after coronary artery ligation. In CHF rats, norepinephrine-induced contractions were increased in intact rings compared with rings from sham rats, despite decreased contraction in denuded rings. Decreased alpha 1-receptor sensitivity was demonstrated by the increased EC50 of methoxamine in endothelium-denuded rings from CHF rats, although maximal responses to KCl contraction were also decreased in CHF. There was no difference in the vascular response to clonidine, and acetylcholine-mediated relaxations were preserved in CHF rats, suggesting normal stimulated nitric oxide release. However, nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester, as well as measurements of basal cGMP, demonstrated that basal nitric oxide release was decreased in CHF rats. CONCLUSIONS: This study demonstrates that the increased vascular responsiveness to norepinephrine in intact vessels from rats with heart failure is the result of decreased basal nitric oxide release and suggests that the dissociation of basal and stimulated nitric oxide release may play a pathophysiology role at an early stage of heart failure.

Animals↗

PubMed1994

Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan).

BACKGROUND: Endothelin (ET) is a potent vasoconstrictor, and its concentration is increased in patients with heart failure. The purpose of this study was to investigate the role of endothelin in heart failure by use of a rat model. METHODS AND RESULTS: Experiments were performed on rats at 1 through 16 weeks after sham operation or coronary artery ligation. Rats with left ventricular end-diastolic pressures > 15 mm Hg were considered to have chronic heart failure (CHF), while the others were considered to have uncomplicated myocardial infarction (MI). There were increased ET-1 concentrations in CHF rats at weeks 1 to 16 (Sham, 20 +/- 0.5 pg/mL, n = 45; CHF, 31 +/- 2 pg/mL, n = 50; P < .001) and transient increases in ET-3 concentrations at week 1 in both the MI and CHF groups. There were no significant increases in big ET-1 concentrations, suggesting an increased conversion of ET-1 from big ET-1 in the CHF group. At weeks 2 through 8, oral administration of the mixed (ETA and ETB) endothelin receptor antagonist bosentan significantly decreased mean arterial pressure in conscious CHF rats, an effect that increased over time. Furthermore, bosentan had an additive effect to the angiotensin-converting enzyme inhibitor cilazapril. CONCLUSIONS: Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evidenced by the significant reduction in mean arterial pressure after oral administration of bosentan. Therefore, endothelin antagonists may be useful therapeutic agents in the treatment of CHF.

Animals↗

PubMed1994

Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries.

Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries and may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET caused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of these receptors mediate this vasoconstriction. To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ETA receptor antagonist BQ-123, and sarafotoxin S6c were performed. Three binding sites were apparent in the left circumflex coronary artery: an ETA receptor, a high-affinity ETB receptor, and a lower-affinity ETB receptor. To investigate the in vivo effects of ETB receptor stimulation, intracoronary sarafotoxin S6c, a highly selective ETB agonist, was administered in anesthetized open-chest dogs in a constant-pressure coronary artery perfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 microgram caused a transient pronounced decrease in coronary resistance. Doses of 1.0 and 3.0 micrograms caused marked decreases in coronary diameter and blood flow, as well as myocardial segmental shortening. These effects of sarafotoxin S6c were not inhibited by constant infusion of BQ-123. The present study demonstrates the presence of ETB receptors in the canine coronary circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of the pathophysiological function of ET in the coronary vasculature and for the development of therapeutically effective ET antagonists.

Animals↗

PubMed1994

Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist.

The authors describe here the pharmacological properties of bosentan, a new nonpeptide mixed antagonist of endothelin (ET) receptors, obtained by structural optimization of the less potent Ro 46-2005 [Ro 46-2005 (4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(3-methoxy-phenoxy)-4-pyrimidinyl ]-benzenesulfonamide]. Bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4-yl]-benzenesulfonamide) competitively antagonized the specific binding of [125I]-labeled ET-1 on human smooth muscle cells (ETA receptors) with a Ki of 4.7 nM and on human placenta (ETB receptors) with a Ki of 95 nM. It also inhibited the binding of selective ETB ligands on porcine trachea. Contractions induced by ET-1 in isolated rat aorta (ETA) and by the selective ETB agonist sarafotoxin S6C in rat trachea were competitively inhibited by bosentan (pA2 = 7.2 and 6.0, respectively), as was the endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery (pA2 = 6.7). The binding of 40 other peptides, prostaglandins, ions and neurotransmitters was not significantly affected by bosentan, which shows its specificity for ET receptors. In vivo, bosentan inhibited the pressor response to big ET-1 both after i.v. and oral administration, with a long duration of action and no intrinsic agonist activity. It also inhibited the depressor and pressor effect of ET-1 and sarafotoxin S6C. Thus, bosentan is the most potent orally active antagonist of ET receptors described so far. Its pharmacological profile makes bosentan a potentially useful drug in the management of clinical disorders associated with vasoconstriction.

Administration, Oral↗

PubMed1993

In vitro characterization of Ro 46-2005, a novel synthetic non-peptide endothelin antagonist of ETA and ETB receptors.

Ro 46-2005 is a new synthetic non-peptide endothelin (ET) receptor antagonist. In binding experiments, Ro 46-2005 proved to be equipotent (IC50 200-500 nM) for inhibition of [125]ET-1 binding on the two known ET receptor subtypes (ETA and ETB). Scatchard analysis was consistent with a competitive binding mode. Ro 46-2005 also inhibited the functional consequences of ET-1 stimulation: the ET-1 induced release of arachidonic acid from rat mesangial cells was inhibited with an IC50 of 1.8 microM.

Animals↗

PubMed1993

Effect of different endothelin receptor antagonists and of the novel non-peptide antagonist Ro 46-2005 on endothelin levels in rat plasma.

The goal of our study was to evaluate and compare the effects of receptor blockade with different endothelin (ET) receptor antagonists on plasma concentrations of ET-1, big ET-1 and ET-3 in conscious rats. Ro 46-2005 10 mg/kg, i.v.), a novel non-peptide antagonist of both ETA and ETB receptors, increased the concentrations of ET-1 in plasma to 200 +/- 13% of basal levels (P < 0.001). This effect was dose- and time-dependent and reached a maximum at 15 min. Ro 46-2005 had no effect on plasma concentrations of big ET-1 and only a minor effect on those of ET-3. In contrast to Ro 46-2005, the selective peptide ETA antagonists BQ-123 and FR-139317 had no effect on plasma ET-1 concentrations. The increase in plasma ET-1 concentrations by Ro 46-2005 was most likely not due to de novo synthesis, since big ET-1 levels were not increased and peak levels were reached early after compound injection, but perhaps to displacement of ET-1 from the ETB receptors.

Animals↗

PubMed1993

Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist.

Since its discovery, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. Plasma concentrations of endothelin-1 are low and its release by endothelial cells is polarized towards the basolateral side, suggesting that it is a paracrine factor and not a hormone. Consequently, the effect of injected endothelin-1 may not reflect the effect of endogenous endothelin-1. In contrast, blockade of the action of endogenous endothelin-1 using receptor antagonists should be a valuable means of investigating its physiological and pathological effects. We report here evidence for the pathophysiological role of endothelin-1 as brought by the first synthetic orally active nonpeptide antagonist of endothelin receptors, Ro 46-2005.

Administration, Oral↗