Pulmonary vascular effects of prostaglandin D2 in newborn pig

Abstract

In the lamb, prostaglandin (PG) D2 dilates the fetal and early neonatal pulmonary vasculature but becomes a constrictor in the older animal. Constriction could result from conversion of PGD2 to 9 alpha,11 beta-PGF2, stimulated formation of an endogenous vasoactive agent, or a change in PGD2 receptor function. An answer to the latter question was sought in the newborn pig using an isolated lung preparation (1, 3, 7 days of age) and the anesthetized, acutely instrumented animal (1 day old). In vitro, PGD2 increased pulmonary vascular resistance (PVR) in a dose- (2-340 ng/g dry lung) and age-dependent fashion under both normoxia (basal or raised tone) and hypoxia. At 1 and 7 days of age, indomethacin (3 X 10(-6) M) blunted the PGD2 constriction by 50%. Likewise, a thromboxane (Tx) A2 receptor antagonist (ONO 3708, 6 X 10(-8) M) curtailed the PGD2 response. In contrast, a TxA2 synthesis inhibitor (OKY 1581, 10(-6) M) was effective (approximately 70% inhibition) only in the 7-day-old animal. 9 alpha,11 beta-PGF2 and PGF2 alpha, also increased PVR in a dose- and age-related manner, although their action was weaker. Conversely, the 9-epoxy,11-methano endoperoxide analogue was the most potent pulmonary vasoconstrictor among the agents tested. In vivo, PGD2 (0.25-1 microgram/kg) constricted both pulmonary and systemic circulations. We conclude that the porcine pulmonary circulation, unlike the lamb circulation, is constricted by PGD2 throughout the neonatal period. This effect is mediated, in part, by a cyclooxygenase product. The increase in the PGD2 response with age cannot be ascribed to conversion to 9 alpha,11 beta-PGF2, since such occurrence would result in reduced effectiveness.