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Biomedical subjects

G A Gray

Publications and source records attributed to G A Gray.

At least 37 records · Page 2Linked to original sources
PubMed1997

Activation of endothelin ETA receptors masks the constrictor role of endothelin ETB receptors in rat isolated small mesenteric arteries.

1. Endothelin-1 (ET-1) produces constriction of the rat mesenteric vascular bed in vivo via ETA and ETB receptor subtypes. The aim of this study was to investigate the relative roles of these receptor subtypes in rat isolated, endothelium-denuded, small mesenteric arteries, under pressure, by use of ET-1; the ETA receptor antagonist, BQ-123; the ETB receptor selective agonist, sarafotoxin S6c (SRTX S6c); the ETB receptor selective antagonist, BQ-788; and the ETA/ETB antagonist, TAK-044. 2. In 3rd generation mesenteric arteries, ET-1 (10(-13)-10(-7) M) produced concentration-dependent contractions (pD2 9.86). SRTX S6c (10(-12)-10(-7) M) also induced concentration-dependent contractions in 53% of arteries studied, although the Emax was much less than that obtained with ET-1 (10.7 +/- 2.9% vs 101.9 +/- 2.6% of the 60 mM KCl-induced contraction). 3. Neither ETB receptor desensitization, by a supra-maximal concentration of SRTX S6c (10(-7) M), nor incubation with BQ-788 (3 x 10(-8) M), had any significant effect on the ET-1 concentration-response curve, although both treatments tended to enhance rather than inhibit responses to ET-1. 4. In the presence of BQ-123 (10(-6) M), responses to low concentrations of ET-1 (up to 10(-10) M) were unaffected but responses to concentrations of ET-1 above 10(-10) M were significantly inhibited. 5. SRTX S6c desensitization followed by incubation with BQ-123 (10(-6) M) or co-incubation with BQ-788 (3 x 10(-8) M) and BQ-123 caused inhibition of responses to all concentrations of ET-1, resulting in a rightward shift of the ET-1 concentration-response curve. The same effect was obtained by incubation with TAK-044 (10(-8) M and 3 x 10(-7) M). 6. Thus, responses of rat small mesenteric arteries to ET-1 are mediated by both ETA and ETB receptors. The relative role of ETB receptors is greater than that predicted by the small responses to SRTX S6c or by resistance of ET-1-induced contraction to ETB receptor desensitization or BQ-788. The effect of ETB receptor desensitization or blockade is only revealed in the presence of ETA receptor blockade, suggesting the presence of a 'crosstalk' mechanism between the receptors. These results support the concept that dual receptor antagonists, like TAK-044, may be required to inhibit completely constrictor responses to ET-1.

Animals↗
PubMed1997

Prolonged effect of a novel S-nitrosated glyco-amino acid in endothelium-denuded rat femoral arteries: potential as a slow release nitric oxide donor drug.

1. The vasodilator properties of a novel S-nitrosated glyco-amino acid (RIG200) were investigated in isolated rat femoral arteries and compared with those of the parent S-nitrosothiol compound, S-nitroso-N-acetylpenicillamine (SNAP). 2. Spectrophotometric analysis revealed that 2.5 mM solutions of RIG200 decomposed more slowly (half-life (t1/2) = 216.2 +/- 26.7 min) than SNAP (t1/2 = 37.2 +/- 13.8 min) in Krebs buffer at 24 degrees C. Furthermore, the rate of decomposition of SNAP, but not of RIG200, was significantly reduced by the Cu(I) chelator, neocuproine. We concluded that the relative stability of RIG200 is due, at least in part, to its resistance to trace Cu(I)-catalyzed decomposition. Nitric oxide (NO) generation from SNAP and RIG200 was confirmed by use of an NO electrode. 3. Experiments to investigate the vasodilator effects of RIG200 were carried out on isolated femoral arteries taken from adult male Wistar rats (400-550 g). Lengths of artery (7-8 mm long) were cannulated, dissected free and perfused at constant flow rate (0.6 ml min-1) with Krebs buffer. Vessels were precontracted with phenylephrine (10.2 +/- 0.3 microM) and developed pressures of 91.8 +/- 4 mmHg, detected upstream by a differential pressure transducer. 4. Concentration-dependent vasodilator responses to bolus injections of SNAP or RIG200 (10 microliters; 10(-8)-10(-3) M) made into the perfusate of endothelium-intact vessels were transient, recovering the preinjection pressure in < 20 min. 5. Responses to equivalent bolus injections of SNAP in endothelium-denuded vessels were also transient but those in response to concentrations of RIG200 > 10(-5) M were sustained. Responses to 10(-3) M RIG200 were sustained for periods > 4 h. Sustained vasodilatation was reversed by the NO scavenger, ferrohaemoglobin (10 microM) but was unaffected by the NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (200 microM), indicating involvement of NO from a source other than NO synthase. 6. We suggest that a possible explanation for the prolonged effect of RIG200 is retention of the compound by the vascular wall, facilitated by endothelial denudation. Slow decomposition of RIG200 in situ would release sufficient NO to maintain a 'vasodilator tone' which persists for more than 4 h. Selective retention by damaged vessels could have important therapeutic implications with regard to targeted delivery of NO, restoring protection to areas deprived of endogenous NO, whilst avoiding unwanted hypotension.

Animals↗
PubMed1997

The contour test of loudness perception.

OBJECTIVE: This article presents the underlying rationale, normative data, and reliability data for a test of loudness perception (the Contour Test) that was devised for use in clinical hearing aid fitting. The Contour Test yields data describing the sound level required for each of seven categories of loudness ranging from very soft to uncomfortably loud. DESIGN: Two experiments are described. Experiment 1 yielded norms for the test. The subjects were 23 male and 22 female normal-hearing listeners. Test stimuli included warble tones at six frequencies and broad band speech. Experiment 2 assessed the reliability of the test results. Ten hearing-impaired listeners responded to the test at two frequencies on two occasions separated by several days. Both experiments also evaluated the effect of using different stimulus increment sizes on the measured levels of loudness categories. RESULTS: Based on the data from experiment 1, norms for each category of each stimulus are reported in terms of mean level and typical between-subject variation in responses. Data are provided in HA-12 cm3 coupler levels as well as in hearing levels (dB HL). The shape of the loudness growth function for warble tones was somewhat different from that for speech. When data were expressed in HL, there were no differences in mean loudness category levels across warble tone test frequencies. Thus, test frequencies were combined and equations were generated to describe the upper and lower limits of typical normal performance for warble tone stimuli. These equations can be used to construct a template for clinical comparison of normative values to patient loudness growth curves. Experiment 2 provided information about the test-retest variability of data yielded by the Contour Test. Reliability appears to be similar to that of the few other category scaling tests described in the literature. Most test-retest differences were 6 dB or less. Although a moderate variation in test increment size did not significantly affect the loudness category levels for young normal-hearing listeners, levels corresponding to loudness categories were significantly higher when larger increments were used with elderly hearing-impaired listeners. CONCLUSIONS: Evidence from this and other research indicates that standardized measurement of loudness perception is an achievable goal for clinical practice. The Contour Test appears to offer a viable approach to clinical measurement of loudness perception: It has good patient acceptance and combines fairly rapid administration with acceptable reliability. Details of test procedures and scoring sheets for manual administration can be downloaded from the Internet at www.ausp.memphis.edu/harl. However, it is important to keep in mind that the application of loudness perception data for narrowband stimuli (such as warble tones) to hearing aid prescription is complicated by the need to account for the effects of loudness summation across bandwidth. There is a need for additional research to establish an empirical link between clinically measured loudness perception and optimal amplification characteristics.

Adolescent↗
PubMed1997

Age-related changes in monosyllabic word recognition performance when audibility is held constant.

Monosyllabic word recognition was studied in 140 subjects between the ages of 20 and 90 years. The subjects were tested under a condition of fixed audibility that was achieved by presenting bandpass-filtered Northwestern University Auditory Test No. 6 (NU-6) word lists at a constant signal-to-noise ratio and limiting threshold losses at the speech frequencies to 25 dB HL. The results indicated the following: (1) Performance did not vary appreciably with age, except among subjects over 70 years. Subjects from 70 to 80 years produced modestly reduced scores (significantly below only the 30-year-old group). Those over 80 years produced significantly lower scores (than all other groups). (2) There were no significant differences in learning or test-retest reliability associated with age. (3) The performance of the oldest subjects could not be explained by differences in speech audibility. Based on these results, a strategy is proposed for correcting predicted word recognition scores for the effects of age.

Adult↗
PubMed1996

Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors.

BACKGROUND: The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ETA receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ETA and ETB receptors in healthy subjects and patients with CHF. METHODS AND RESULTS: Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF was measured by venous occlusion plethysmography. In CHF patients (n = 10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ETA receptor antagonist) increased FBF by 52 +/- 10% (P = .0006) and 31 +/- 6% (P = .002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15 +/- 5% (P = .0007). Forearm vasoconstriction to endothelin-1 (an ETA and ETB receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n = 10; CHF versus control subjects, P < .001), whereas vasoconstriction to sarafotoxin S6c (an ETB receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n = 10; CHF versus control subjects. P < .05). CONCLUSIONS: ECE inhibitors and ETA receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ETA and ETB receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.

Aged↗
PubMed1996

Cross-correlation effects on NMR lineshapes and peptide conformation.

Information about molecular structure and dynamics can potentially be obtained by studying dipole-dipole and chemical-shift anisotropy (CSA) auto-correlation and dipole-CSA cross-correlation effects in high-resolution NMR spectra. Equations for the lineshapes of the HN multiplet in the fragment- 15NH-CH- as a function of NH-CH dihedral angle are derived by including these effects within the framework of the Redfield treatment of relaxation. To test the utility of the theoretical results, 1H[15N] HSQC proton lineshape data for a variant of the enzyme staphylococcal nuclease in which all valine residues are labeled with 15N have been analyzed to obtain the conformational angle (phi) between the N-H and adjacent C-H bonds. The results are generally in good agreement with values of phi obtained from crystal structure data. Considerations in the further development of the analysis of the lineshape of the HN multiplet for experimental determinations of phi are discussed.

Algorithms↗
PubMed1996

The endothelin system and its potential as a therapeutic target in cardiovascular disease.

Endothelin (ET)-1, an endothelium-derived peptide, is the most potent vasoconstrictor agent described to date. ET-1 also has positive inotropic and chronotropic effects in the heart and is a co-mitogen in both cardiac and vascular myocytes. The major elements of the system involved in formation of ET-1 and its isopeptides, as well as the receptors mediating their effects, have been cloned and characterised. Antagonists of the ET receptors are now available, and selective inhibitors of the ET-converting enzymes are being developed. Early studies using receptor antagonists support the involvement of ET-1 in the pathophysiology of several cardiovascular diseases. The relative merits of ET-converting enzyme inhibitors and receptor antagonists for the treatment of cardiovascular disease are discussed.

Amino Acid Sequence↗
PubMed1996

Benefit acclimatization in elderly hearing aid users.

A previous study from this laboratory indicated that the benefit obtained from a hearing aid in a noisy environment might increase over the first few months of hearing aid use. It was hypothesized that this acclimatization of benefit was due to a process in which the individual optimized his/her use of modified or newly available high-frequency acoustic speech cues. This investigation further explored the effect in 22 elderly individuals with mild to moderate sensorineural hearing losses, fitted unilaterally with hearing aids. None of the subjects was a current or recent hearing aid wearer. Speech intelligibility testing over a 12-week post-fitting period indicated that a significant improvement in benefit was seen for the group as a whole, probably beginning after about 6 weeks of regular hearing aid use. However, the magnitude of improvement was very small for most subjects. Only three individuals experienced a dramatic improvement in their benefit for speech in noise over this period. No evidence was found for a specific role of high-frequency cues. Seven subjects participated in a long-term follow-up in which benefit was measured after several months of use of their newly acquired personal hearing aids. Further increase in benefit was noted but was due exclusively to a decline in performance for unaided listening.

Aged↗
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

Structural changes and cyclic GMP content of the aorta after calcium antagonism or angiotensin converting enzyme inhibition in renovascular hypertensive rats.

OBJECTIVE: To evaluate the respective roles of elevated blood pressure and stimulation of the renin-angiotensin system in the development of structural changes in the aortae of rats with renovascular hypertension. MATERIALS AND METHODS: Renovascular hypertensive rats (two-kidney, one clip) were randomly allocated to three different groups and were treated with equihypotensive doses of an angiotensin converting enzyme (ACE) inhibitor (enalapril, 3 mg/kg per day) or of a new long-acting calcium antagonist (mibefradil, 30 mg/kg per day). A renovascular hypertensive group was left untreated. A sham-operated group of rats was used as a normotensive control group. At the end of the 5-week treatment period the rats were killed and their aortae were removed. Medial hypertrophy, elastin and collagen content and density of nuclei were evaluated using quantitative morphometry. The aortic cyclic GMP (cGMP) content was quantified by radioimmunoassay. RESULTS: Hypertension was associated with medial hypertrophy, a decreased elastin: collagen ratio, hypertrophy of the smooth muscle cells and increased cGMP content of the aorta. Mibefradil and enalapril equally prevented the morphological consequences of hypertension (i.e. medial hypertrophy and the decreased elastin:collagen ratio). The aortic cGMP content was increased by enalapril but not by mibefradil. CONCLUSION: The present results show that, even in a high-renin model (two-kidney, one clip), it is possible to prevent or suppress the vascular consequences of hypertension without interfering with the renin-angiotensin system. This suggests that the changes observed in the aorta are directly related to blood pressure or to other mechanisms independent of the renin-angiotensin system, which could be blocked by a calcium antagonist such as mibefradil.

Angiotensin-Converting Enzyme Inhibitors↗
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

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↗
PubMed1995

Forearm vasoconstriction to endothelin-1 is mediated by ETA and ETB receptors in vivo in humans.

The role of endothelin (ET)-B (ETB) receptors in mediating vasoconstriction in humans is unclear. As yet, in vitro data have been contradictory, and there have been no in vivo studies in resistance vessels. We investigated the function of ETB receptors in vivo in human forearm resistance vessels using ET-1 as a nonselective agonist at ETA and ETB receptors and ET-3 and sarafotoxin S6c as ETB receptor agonists. Brachial artery infusion of ET-1 and ET-3 caused slow-onset, dose-dependent forearm vasoconstriction. Although ET-3 caused significantly less forearm vasoconstriction than ET-1 at low doses, vasoconstriction to the two isopeptides was similar at the highest dose (60 pmol/min). ET-3 caused initial transient forearm vasodilatation at this dose, whereas ET-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to ET-1. Therefore, ETB receptor agonists contract human resistance vessels in vivo. The effects of ET-3 and sarafotoxin S6c, compared with ET-1, suggest that both ETA and ETB receptors mediate vasoconstriction. Antagonists at both ETA and ETB receptors, or inhibitors of the generation of ET-1, may be necessary to completely prevent vasoconstriction to endogenously generated ET-1.

Adult↗
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

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

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↗