Nitric oxide(NO) and α-adrenergic reactivity of developing cerebral arteries: role of α₁- and α₂- adrenoceptor subtypes ♦ 339

Nitric oxide is an important endogenous inhibitor of norepinephrine(NE)-induced contraction accounting in part for the maturational decrease in NE sensitivity (i.e. ↑EC₅₀) and in maximal force generated (Fmax) in ovine cerebral arteries. In fetal (F) and newborn (NB) sheep cerebral arteries, NE-induced contraction appears to be mediated byα₁-adrenoceptors while the role of α₂-adrenoceptors is not well characterized. However, α₂-adrenoceptors have been demonstrated in cerebral arteries of some species. In order to evaluate the relative role of α-adrenoceptor subtypes and their susceptibility to attenuation by NO, we studied the effect of NO synthase inhibitor, N^G-nitro-L-arginine methyl ester (L-NAME), on the contractile response to α₁- and α₂-adrenoceptor agonists, phenylephrine (PE) and UK 14304. Middle cerebral artery (MCA) rings from five F (125 d gest, 9 vessels) and three NB (3-7 d, 6 vessels) lambs were evaluated for isometric contraction using organ baths. Contractile reactivity to UK 14304 was poorly expressed in NB and F MCAs under control conditions; only 1/5 of NB and 3/8 of F MCAs responded. However, L-NAME (100 μM) dramatically enhanced the contractile response to this α₂-agonist in both NB and F MCAs; 4/5 of NB and 8/8 of F responded (Fmax = 25±9 and 32±7% KCl(120 mM); EC₅₀=45 and 50 nM, respectively). Theα₁-agonist, PE, caused a dose-dependent contraction in both NB and F MCAs (Fmax=54±9 and 57±8% KCl, respectively). However, NB was three-fold less sensitive than F (EC₅₀=1.30 μM vs 0.43 μM, respectively). L-NAME increased the sensitivity to PE in both NB and F MCA(EC₅₀=0.55 μM and 0.23 μM, respectively) but not the Fmax. It is concluded that: 1) both α₁- and α₂-adrenoceptors are expressed in the developing ovine MCA, 2) NO attenuates bothα-adrenoceptor responses but α₂-mediated contraction is most sensitive. The interplay between α₂-stimulated endothelial NO production and smooth muscle contraction is pivotal to the ultimate adrenergic response. Accordingly, an immature or dysfunctional endothelium may significantly augment sympathetic reactivity via α₂-dependent mechanisms.