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 alpha 1-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 (approximately 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, 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.