Vol. 302, Issue 2, 672-680, August 2002

The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

Yashu Coe, Stephen J. Haleen, Kathleen M. Welch, You-An Liu and Flavio Coceani

Department of Paediatrics, University of Alberta, Edmonton, Alberta, Canada (Y.C.); Department of Cardiovascular Therapeutics, Pfizer, Ann Arbor, Michigan (S.J.H., K.M.W.); and Integrative Biology Programme, Hospital for Sick Children, Toronto, Ontario, Canada (Y.-A.L., F.C.)

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 A₂ analog, 9,11-epithio-11,12-methano-thromboxane A₂ (ONO-11113) was instead not amenable to ET_AR 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.