Trends in Pharmacological Sciences
Meeting reportCalifornia dreamin' 'bout endothelin: emerging new therapeutics
Abstract
Progress in our understanding of endothelins has been extremely rapid since their discovery in 1988. A number of pharmaceutical companies have developed potent, orally active, nonpeptide endothelin receptor antagonists with efficacies in a wide variety of animal disease models and potential for treating human disease. However, only time will tell whether or not these compounds are developed into drugs that are perceived as worthy of a place in the therapeutic marketplace. If this is the case, endothelin will have been promoted from the status of striking scientific discovery to therapeutic target in a remarkably short period.
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Effect of SB 217242 on hypoxia-induced cardiopulmonary changes in the high altitude-sensitive rat
1999, Pulmonary Pharmacology and TherapeuticsThe effects of SB 217242, a non-peptide endothelin (ET) receptor antagonist, were investigated against hypoxia-induced cardiopulmonary changes in high altitude-sensitive rats. In isolated pulmonary artery rings, SB 217242 (30 n) antagonized ET-1-induced contractions with apKBof 8.0. There was no difference in the sensitivity to ET-1 or the potency of SB 217242 in pulmonary artery from normoxic rats vs. rats exposed to hypoxia (9% O2) for 14 days. However, there was a marked reduction in the maximum response to ET-1, but not to KCl or phenylephrine, in pulmonary artery from hypoxic rats; this phenomenon was inhibited by treatment of animals with SB 217242 (10.8 mg/day, ip by osmotic pump) for the 14-day hypoxic period. Furthermore, there was a significant reduction in carbachol-induced, endothelium-dependent relaxation of precontracted pulmonary artery from hypoxic animals; SB 217242 treatment during the hypoxic period did not influence this difference. Vehicle-treated rats exposed to 14-day hypoxia had 173% higher pulmonary artery pressures and 75% higher right/left+septum ventricular mass ratios compared to normoxic animals. SB 217242 (3.6 or 10.8 mg/day, ip) markedly reduced (80 and 95%, respectively) hypoxia-induced increases in pulmonary artery pressure. Right ventricular hypertrophy was inhibited by 40% at the 10.8 mg/day dose. Marked medial thickening and luminal stenosis of small and medium-sized pulmonary arteries was observed in hypoxic rats. The SB 217242-treated, hypoxia-exposed rats had comparable small and medium-sized arteries to normoxic rats. Rats treated with SB 217242 (10.8 mg/day) for the last 14 days of a 28-day hypoxic exposure had significantly lower pulmonary artery pressures than those of vehicle-treated rats. In addition, the effects of the selective ETAreceptor antagonist, SB 247083, and the selective ETBreceptor antagonist, A-192621 (3.6 or 10.8 mg/day, ip), were compared against hypoxia-induced increases in pulmonary artery pressure and plasma ET concentrations. SB 247083, but not A-192621, inhibited hypoxia-induced pulmonary hypertension, whereas A-192621, but not SB 247083, significantly exacerbated hypoxia-induced increases in ET concentrations, suggesting that hypoxia-induced pulmonary pressor responses are mediated via ETAreceptor activation, while ETBreceptor blockade may alter clearance of hypoxia-induced elevated plasma ET. The inhibitory effects of SB 217242 on the functional and remodeling changes induced by hypoxia provide further evidence that ET may play a central role in pulmonary hypertension and that ET receptor antagonists may have a utility in the treatment of this disease.
Mechanisms of hyperoxia-induced reductions in retinal blood flow in newborn pig
1998, Experimental Eye ResearchAlthough reductions in retinal blood flow (RBF) in response to acute hyperoxia are well described, the mechanistic basis of this response has yet to be clarified. The present study was undertaken in order to determine the possible involvement of two arachidonic acid-derived vasoconstrictors, the cyclooxygenase metabolite thromboxane and the cytochrome P450metabolite 20-HETE, as well as the involvement of the peptide endothelin and superoxide free radical. Fluorescein videoangiography was performed on the intact eyes of isoflurane-anesthetized newborn piglets. RBF responses to 20 min of hyperoxia were calculated from the angiograms off-line, using changes in mean arteriovenous transit times and arteriolar and venular diameters. The effect of hyperoxia (PaO2=351±9 mmHg;n=39) on RBF was examined in each animal under control conditions and again after intravitreal perivascular administration of drugs that block the synthesis or receptors of known vasoconstrictors. Estimated RBF decreased by a maximum of 42±3% in the 7 animal groups in response to 20 min of hyperoxia. The magnitude and time course of the change in RBF resulting from two successive hyperoxic challenges did not differ, and were unaffected by intravitreal administration of vehicle. The response to hyperoxia was attenuated 46±6 (n=6;P=0.001) after intravitreal CGS 22652 (2 nmol), a combined thromboxane synthesis inhibitor and receptor antagonist. DDMS (12.5 nmol), a competitive inhibitor of the P450enzyme ω-hydroxylase that forms 20-HETE, blocked hyperoxic constriction by 23±7% (n=6;P=0.01). Intravitreal pretreatment with TBC 1241z (2 nmol), a receptor antagonist of the peptide endothelin, blocked the hyperoxic response by 26±5% (n=6;P=0.01). A combination of CGS 22652 (2 nmol), DDMS (12.5 nmol), and TBC 1241z (2 nmol), blocked the hyperoxic flow response by 51±3% (n=5;P=0.003). Administration of a combination of superoxide dismutase (10 U intravitreally, 10000 U kg-1of the polyethylene glycol-conjugate intravenously) and catalase (10 U intravitreally, 10000 U kg-1intravenously) was without effect on hyperoxia-induced reductions in RBF (n=5). The present results indicate that the arachidonic acid metabolites thromboxane and 20-HETE, and the peptide endothelin, participate in mediating the acute reduction in RBF in response to hyperoxia.
Cardiovascular activity of naturally occurring lignans
1997, PhytomedicineThe activities of lignans and neolignans which directly or indirectly affect the cardiovascular system are reviewed. The results from molecular screening methods and animal models are included and an attempt to identify the molecular features which might influence some of the activities is made. The question of the benefit of low levels of circulating lignans in an organism is considered.
Physiological role of brain endothelin in the central autonomic control: From neuron to knockout mouse
1997, Progress in NeurobiologyAlthough endothelin (ET) was discovered as a potent vascular endothelium-derived constricting peptide, its presumed physiological and pathophysiological roles are now considered much more diverse than originally thought. Endothelin in the brain is thought to be deeply involved in the central autonomic control and consequent cardiorespiratory homeostasis, possibly as a neuromodulator or a hormone that functions locally in an autocrine/paracrine manner or widely through delivery by the cerebrospinal fluid (CSF). This notion is based on the following lines of evidence.
(1) Mature ET, its precursors, converting enzymes, and receptors all are detected at strategic sites in the central nervous system (CNS), especially those controlling the autonomic functions. (2) The ET is present in the CSF at concentrations higher than in the plasma. (3) There is a topographical correspondence of ET and its receptors in the CNS. (4) The ET is released by primary cultures of hypothalamic neurons. (5) When ET binds to its receptors, intracellular calcium mobilization occurs in neurons and glia via phospholipase C activation and/or by opening calcium channels. (6) An intracerebroventricular or topical application of ET to CNS sites elicits a pattern or cardiorespiratory changes accompanied by responses of vasomotor and respiratory neurons. (7) Recently generated knockout mice with disrupted genes encoding ET-1 exhibited, along with malformations in a subset of the tissues of neural crest cell lineage, cardiorespiratory abnormalities including elevation of arterial pressure, sympathetic overactivity, and impairment of the respiratory reflex.
Definitive evidence is expected from thorough analyses of knockout mice by applying conventional experimental methods. © 1997 Elsevier Science Ltd. All Rights Reserved.
Role for nuclear factor-κB and signal transducer and activator of transcription 1/interferon regulatory factor-1 in cytokine-induced endothelin-1 release in human vascular smooth muscle cells
2003, Molecular PharmacologyPharmacokinetics of SB-247083, a potent and selective endothelin<inf>A</inf> receptor antagonist, in the rat, dog and monkey
2002, Biopharmaceutics and Drug Disposition