The endothelin A receptor antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) reverse the hypoxic pulmonary vasoconstriction in the perinatal lamb.

Endothelin-1 (ET-1) is considered an intermediary in the constrictor response of the pulmonary vasculature to hypoxia and, by extension, is assigned a prime role in the pathogenesis of pulmonary hypertension. We report here the antihypertensive action in the conscious newborn lamb of two novel endothelin A receptor antagonists, sodium 2-benzo-[1,3]dioxol-5-yl-4- (4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2- enoate (PD 156707) and 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1, 1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1l6-benzo-[e][1,2]thiazine-3-carboxylic acid potassium (PD 180988), differing in chemical properties and half-life within the body. PD 156707 and PD 180988, given in the right atrium as a bolus followed by infusion, had little or no effect on pulmonary and systemic hemodynamics under normoxia.

ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells.

We determined the distribution of ET(A) and ET(B) receptors in pulmonary arteries from pulmonary hypertensive patients and control subjects, using in vitro autoradiography, and investigated their role in mediating the proliferative effects of endothelin-1 (ET-1) on distal human pulmonary artery smooth muscle cells (PASMCs). Distal arteries possessed more medial [(125)I]-ET-1 binding sites (105 +/- 10 versus 45 +/- 6 amol/mm(2); p < 0.001) and a greater proportion of ET(B) receptors than proximal arteries (36 +/- 3% versus 3 +/- 1%; p < 0.

Defective intracellular calcium handling in monocrotaline-induced right ventricular hypertrophy: protective effect of long-term endothelin-A receptor blockade with 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080).

We studied the effect of long-term treatment with the oral endothelin (ET) ET(A) antagonist 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-sodium (PD 155080; PD) on right ventricular intracellular calcium (Ca(2+)(i)) handling and cardiac and pulmonary artery function in control rats and rats with monocrotaline (MCT)-induced right-heart hypertrophy. Rats were given an intraperitoneal injection of either saline (controls; n = 9) or MCT (50 mg/kg; n = 12), resulting in pulmonary hypertension-induced myocardial hypertrophy, or MCT followed by the daily administration of PD (50 mg/kg) for 9 weeks (n = 9). After 9 weeks, right ventricular pressure was measured, and the hearts were removed and perfused in vitro.

Studies on coronary arteriopathy in dogs following administration of CI-1020, an endothelin A receptor antagonist.

A selective nonpeptide endothelin A (ETA) receptor antagonist, CI-1020, was administered to beagle dogs intravenously (i.v.) for 4 hours to 4 weeks.

The endothelin-A-receptor antagonist PD 180988 (CI-1034) selectively reverses the pulmonary vasoconstrictor response to hypoxia in the lamb.

Endothelin-1 (ET-1) is assigned a mediator role in the constrictor response of the pulmonary vasculature to hypoxia. Accordingly, a recently developed endothelin-A (ETA) antagonist, PD180988, was tested in the chronically instrumented newborn lamb to verify this possibility and, at the same time, to study a potential new treatment for pulmonary hypertension (PH). PD180988, given by infusion after a priming bolus, had an insignificant effect on the pulmonary circulation under normoxia, while it reversed the sustained pulmonary constriction caused by hypoxia.