Nitric Oxide and β-Adrenergic Mechanisms Modify Contractile Responses to Norepinephrine in Ovine Fetal and Newborn Cerebral Arteries

ABSTRACT: Ovine fetal cerebral arteries exhibit an enhanced contractile response to norepincphrine (NE) compared with newborns and adults. It is possible that β-adrenergic receptors and/or nitric oxide (NO), a putative endothelium-dependent relaxing factor, differentially modulate cerebrovascular responsiveness to NE as a function of development. The present study evaluated the effect of the β-adrenoceptor antagonist, propranolol, and the NO synthase inhibitor, NG-nitro-1.-arginine methyl ester (LNAME), on the contractile response of isolated middle cerebral artery (MCA) and basilar artery (BA) to NE during fetal development. MCAs isolated from four preterm fetal lambs (105 d of gestation), seven near-term fetal lambs (125–130 d of gestation), and eight newborn lambs (2–7 d of age) were evaluated using organ baths. BAs isolated from the near-term fetal and newborn lambs were also evaluated. Contractile reactivity of MCAs to NE decreased significantly during fetal maturation as manifested by a marked decrease in Fmax (maximal relative contractile force generated) and an increase in EC50 (Fmax - 100 ± 7, 41 ± 7, and 28 ± 8% of KCl contraction; EC50 - 0.14 ± 0.03, 1.09 ± 0.36, and 1.07 ± 0.22 μM for preterm fetus, near-term fetus, and newborn lamb MCAs, respectively, p < 0.05). Propranolol treatment (10-5 M) increased Fmax (2-fold) only for newborn lamb MCAs. Pretreatment with LNAME (10 4M) markedly enhanced the contractile response to NE (7-fold decrease in EC50 and 2-fold increase in Fmax, P < 0.05) for near-term fetus MCAs, whereas preterm fetus and newborn lamb MCAs were unaffected by the inhibitor. BAs were unresponsive to NE except for near-term fetus BAs in the presence of LNAME. The effect of NO-synthase inhibition on NE contractility was dependent on developmental age, being prominent near term. The data suggest that, in the more mature fetus, NO, presumably derived from endothelium, behaves as a functional antagonist to sympathetic vasoconstriction of the cerebrovasculature, and its apparent absence permits unrepressed sympathetic vasoconstriction in the premature brain.