Ins(1,4,5)P₃ receptors in cerebral arteries: Changes with development and high-altitude hypoxia

We and others have shown that adrenergic-mediated contractile responses in cerebral vessels in vitro differ with vessel segment, with developmental age, and with high-altitude, long-term hypoxia. This is associated with significant differences in α₁-adrenergic receptor density and norepinephrine (NE)-induced response of the second messenger inositol 1,4,5- trisphosphate [Ins(1,4,5)P₃]. To test the hypothesis that vessel-specific, developmental, and hypoxic-associated contractility changes are mediated, in part, by changes in Ins(1,4,5)P₃-receptor [Ins(1,4,5)P₃-R] density or affinity, we performed the following study. In common carotid (Com), circle of Willis, and main branch anterior, middle, and posterior cerebral arteries (MBC) from normoxic fetal (~140 days), newborn (3-5 days), and adult sheep and fetal and adult sheep acclimatized to high altitude, we quantified Ins(1,4,5)P₃-R with [³H]Ins(1,4,5)P₃. In normoxic Com, Ins(1,4,5)P₃-R density values (fmol/mg protein) in fetus, newborn, and adult were 8 ± 53, 150 ± 18, and 357 ± 21, respectively (P < 0.05). In normoxic MBC cerebral arteries, the receptor density values in the three age groups were 115 ± 15, 105 ± 9, and 99 ± 5 fmol/mg protein, respectively. For fetal and adult Com, high-altitude, long-term hypoxemia was associated with decreases in Ins(1,4,5)P₃-R density of 32 (to 58 ± 5) and 70% (to 109 ± 12), respectively, from control values (P < 0.01). In MBC cerebral arteries of fetus and adult, hypoxic-associated decreases in Ins(1,4,5)P₃-R density from control were 80 (to 23 ± 3) and 47% (to 53 ± 7), respectively (P < 0.01). Ins(1,4,5)P₃ binding affinity to the receptor averaged 11.8 ± 0.5 nM and did not vary significantly as a function of vessel type, developmental age, or hypoxia. In Com, but not in MBC, Ins(1,4,5)P₃-R density increased dramatically with developmental age. This suggests that differences in Ins(1,4,5)P₃-R density values may account, in part, for differences in contractile responses of the two artery types in the several age groups. In response to long-term, high-altitude hypoxia, Ins(1,4,5)P₃- R density values in both fetal and adult Com and MBC decreased significantly, as did their NE-induced contraction. This suggests a cellular basis for changes in cerebrovascular contractility in response to long-term hypoxia and that Ins(1,4,5)P₃-R may play a role in acclimatization responses to high altitude.