Ontogeny of β-Adrenergic Regulation of Adenylate Cyclase in Intrapulmonary Arteries from Fetal and Postnatal Lambs

Abstract

ABSTRACT: The enzyme adenylate cyclase is critically involved in the regulation of vasodilatation in the developing pulmonary circulation in that it mediates the vascular smooth muscle effects of β-adrenergic agonists and vasodilatory prostaglandins. These agonists activate receptors coupled to the catalytic subunit of the enzyme by stimulatory guanine nucleotide-dependent regulatory proteins. We examined the ontogeny of the function of the adenylate cyclase system in intrapulmonary arterial segments from fetal lambs at 110–115 (F1) and 125–135 d gestation (F2) and from postnatal lambs at 7–14 (P1) and 35–56 d of age (P2). The function of the intact enzyme system and its components was assessed in incubations measuring cAMP accumulation during phosphodiesterase inhibition. β-Adrenergic mediation of adenylate cyclase was examined because the binding characteristics of the smooth muscle receptors can be readily quantified. Nonstimulated (basal) cAMP accumulation was similar in F1 and F2, it increased 8-fold from F2 to P1, and it was equivalent in P1 and P2. cANIP accumulation with isoproterenol increased 5.9-fold from F1 to F2 and was similar in F2, P1, and P2. Radioligand binding studies revealed that the greater response to isoproterenol in F2 versus F1 is not related to an increase in β-adrenergic receptor density or affinity. cAMP accumulation with forskolin, which activates adenylate cyclase by actions that involve both the stimulatory guanine nucleotide-dependent regulatory protein and the catalytic subunit, was similar in the four age groups, indicating that there are no maturational changes in the function of these enzyme system components. As such, the enhancement in β-adrenergic mediation of the enzyme during the 3rd trimester may be related to changes in receptor-guaninne nucleotide-dependent regulatory protein coupling. It is concluded that there are marked developmental alterations in the function of the adenylate cyclase system in the intrapulmonary arteries during late gestation that may serve to optimize the capacity of this mediator of pulmonary vasodilatation in the perinatal period.