High altitude, hypoxic-induced changes in [alpha]1-adrenergic receptors and ins(1,4,5)p3 responses in fetal and adult cerebral arteries. Ueno, Nobumi, Yu Zhao, Lubo Zhang, and Lawrence D. Longo. Center for Perinatal Biology, Departments of Physiology, Pharmacology, and Obstetrics and Gynecology, Loma Linda University School of Medicine, Loma Linda, CA 92350
APStracts 3:0319R, 1996.
Background. 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 hypoxic-induced developmental and vessel specific cerebral artery contractility changes are mediated, in part, by changes in [alpha]1-adrenergic receptor ([alpha]1-AR) density and/or NE-induced inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) responses, we performed the following study. Methods. In common carotid (COM) and combined anterior, middle, and posterior (AMP) cerebral arteries from normoxic adult ewes and near-term fetuses, and those acclimatized to high altitude (3,820 m), we quantified [alpha]1-AR density (Bmax in fmol/mg protein) and affinity (KD in nM) with the [alpha]1-AR antagonist [3H]prazosin. In addition, we quantified norepinephrine -induced Ins(1,4,5)P3 responses in these arteries. Results. With long -term hypoxemia, [alpha]1-AR density in fetal and adult COM decreased 75% (from 113+/-18 to 28+/-5) and 66% (from 54+/-3 to 18+/-4), respectively, from normoxic control values. [alpha]1-AR density of the fetal and adult AMP decreased 76% (from 47+/-4 to 11+/-1) and 61% (from 23+/-3 to 9+/-3), 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 AMP, 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. Conclusions. 1) In the adult COM and AMP cerebral vessels, acclimatization to high altitude, long-term hypoxemia was associated with significant decreases in both [alpha]1 -AR density values and Ins(1,4,5)P3 responses to NE. Similarly in the fetal AMP cerebral arteries, high altitude hypoxemia was associated with marked attenuation of both [alpha]1-AR density and NE-induced Ins(1,4,5)P3 responses. 2) The magnitude of decreases in NE-induced Ins(1,4,5)P3 responses in these vessels correlated fairly well with the decreases in [alpha]1-AR density. 3) 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. 

Received 8 April 1996; accepted in final form 12 August 1996.
APS Manuscript Number R197-6.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 19 September 1996