Long-Term Hypoxic-Induced Changes in Inositol 1,4,5-Trisphosphate Receptor Density in Fetal and Adult Ovine Cerebral Arteries. † 1344

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Background. In response to high altitude long-term hypoxia, the cerebral arteries of fetal and adult sheep show decreased contractile responses to K+ depolarization and amines (Am. J. Physiol. 264:R65-R72, 1993). This is associated with markedly attenuated density ofα1-adrenergic receptors and their second messenger inositol 1,4,5-trisphosphate (InsP3) (submitted). To test the hypothesis that hypoxic-induced changes in developmental and vessel specific cerebral artery contractility are mediated, in part, by changes in IP3-receptor(IP3R) density and/or affinity, we performed the following study.Methods. In aorta, common carotid artery, circle of Willis, and cerebral arteries from both near-term fetuses and adult ewes, we quantified IP3R density (fmol/mg protein) and affinity (nM) by saturation binding with [3H]IP3 (n=4 to 6 assays per group. * indicates a p value of < 0.05 for hypoxia vs normoxia). Results. For fetal and adult aorta, long-term hypoxemia was associated with decreases of in IP3R density of 46% (109 to 59) and 66%* (181 to 62), respectively. In the common carotid artery, IP3-R density for fetus and adult decreased 32%* (85 to 58) and 69%* (357 to 109), respectively. In cerebral arteries of fetus and adult, hypoxic-associated IP3-R densities decreased 80%* (128 to 25) and 46%* (99 to 53), respectively. The IP3 binding affinity was not changed among the groups studied. Conclusions. 1) IP3R values in fetal and adult aorta, common carotid, and combined anterior, middle, and posterior cerebral arteries, all decreased significantly in response to long-term hypoxia. 2) The decrease in fetal IP3-receptor density was of the same order of magnitude as that of the adult. This suggests that despite“buffering” by the maternal organism, fetal vascular tissues sensed hypoxia in a manner similar to that of the adult. 3) These findings suggest a cellular basis for changes in cerebrovascular contractility in response to long-term hypoxia, and that IP3-receptors may play a role in certain acclimatization responses to high altitude. (Supported in part by USPHS Grant HD 03807)