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

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)