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. 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.
Department of Paediatrics, University of Alberta, Edmonton, Alberta, Canada.
Yashu
Y
Coe
Stephen J
SJ
Haleen
Kathleen M
KM
Welch
You-An
YA
Liu
Flavio
F
Coceani
D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D000860:Hypoxia; D066298:In Vitro Techniques; D007700:Kinetics; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D044022:Receptor, Endothelin A; D012756:Sheep; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; C093321:PD 156707; D044022:Receptor, Endothelin A