High altitude-induced changes in α₁-adrenergic receptors and Ins(1,4,5)P₃ responses in cerebral arteries

In response to high-altitude long-term hypoxemia, the cerebral arteries of fetal and adult sheep show decreased contractile responses to norepinephrine (NE) and other agonists. To test the hypothesis that hypoxia- induced developmental and vessel specific cerebral artery contractility changes are mediated, in part, by changes in α₁-adrenergic receptor (α₁- AR) density and/or NE-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] responses, we performed the following study. In common carotid (Com) and main branch cerebral (MBC) arteries from normoxic adult ewes and near-term fetuses and those acclimatized to high altitude (3,820 m), we quantified α₁-AR density (maximal binding in fmol/mg protein) and affinity (dissociation constant in nM) with the α₁-AR antagonist [³H]prazosin. In addition, we quantified NE-induced Ins(1,4,5)P₃ responses in these arteries. With long- term hypoxemia, α₁-AR density in fetal and adult Com decreased 75% (from 113 ± 18 to 28 ± 5 fmol/mg protein) and 66% (from 54 ± 3 to 18 ± 4 fmol/mg protein), respectively, from normoxic control values. α₁-AR density of the fetal and adult MBC decreased 76% (from 47 ± 4 to 11 ± 1 fmol/mg protein) and 61% (from 23 ± 3 to 9 ± 3 fmol/mg protein), respectively, from controls. In hypoxemic adult Com, the NE-induced Ins(1,4,5)P₃ response decreased 51% (from 309 ± 38 to 151 ± 24%) from the control value. In fetal and adult MBC, long-term hypoxemia was associated with decreases of 35% (from 345 ± 40 to 225 ± 30%) and 44% (from 355 ± 55 to 199 ± 16%), respectively, from control values. We conclude that in the adult Com and MBC vessels, acclimatization to high-altitude, long-term hypoxemia was associated with significant decreases in both α₁-AR density values and Ins(1,4,5)P₃ responses to NE. Similarly, in the fetal MBC arteries, high-altitude hypoxemia was associated with marked attenuation of both α₁-AR density and NE-induced Ins(1,4,5)P₃ responses. The magnitude of decreases in NE-induced Ins(1,4,5)P₃ responses in these vessels correlated fairly well with the decreases in α₁-AR density. These findings suggest that changes in noradrenergic receptor-second messenger coupling may play a role in altered cerebrovascular tone in association with high-altitude acclimatization and other forms of long-term hypoxia in both fetus and adult.