内皮素受体
药理学
敌手
化学
硝苯地平
脑血管痉挛
血管痉挛
受体
医学
内科学
内分泌学
蛛网膜下腔出血
钙
作者
Sébastiên Roux,Volker Breu,Thomas Giller,Werner Neidhart,Henri Ramuz,Philippe Coassolo,J. P. Clozel,Martine Clozel
出处
期刊:PubMed
日期:1997-12-01
卷期号:283 (3): 1110-8
被引量:23
摘要
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.
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