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. Conversely, they both reversed the
pulmonary hypertension due to alveolar
hypoxia while producing minor changes, or no change at all, in systemic vascular resistance. Furthermore, their pulmonary vascular effect outlasted administration.
Pulmonary hypertension being elicited by infusion of the
thromboxane A(2) analog, 9,11-epithio-11,12-methano-thromboxane A(2) (ONO-11113) was instead not amenable to ET(A)R inhibition. Blood levels of ET-1, which rose with
hypoxia but not
ONO-11113 treatment, were not changed by either antagonist. Consistent with findings in vivo, when using isolated pulmonary resistance arteries from term fetal lamb,
PD 156707 curtailed the
hypoxia- but not the ONO-11113-induced constriction. We conclude that
PD 156707 and
PD 180988 are selective inhibitors of pulmonary vasoconstriction resulting from
hypoxia. Our findings support the use of these or allied compounds in the management of
pulmonary hypertension in the neonate.