INS(1,4,5)P-3 RECEPTORS IN CEREBRAL-ARTERIES - CHANGES WITH DEVELOPMENT AND HIGH-ALTITUDE HYPOXIA

We and others have shown that adrenergic-mediated contractile response s in cerebral vessels in vitro differ with vessel segment, with develo pmental age, and with high-altitude, long-term hypoxia. This is associ ated with significant differences in alpha(1)-adrenergic receptor dens ity and norepinephrine (NE)-induced response of the second messenger i nositol 1,4,5-trisphosphate [Ins(1,4,5)P-3]. To test the hypothesis th at vessel-specific, developmental, and hypoxic-associated contractilit y changes are mediated, in part, by changes in Ins(1,4,5)P-3-receptor [Ins(1,4,5)P-3-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 (si milar to 140 days), newborn (3-5 days), and adult sheep and fetal and adult sheep acclimatized to high altitude, we quantified Ins(1,4,5)P-3 -R with [H-3]Ins(1,4,5)P-3. In normoxic Com, Ins(1,4,5)P-3-R density v alues (fmol/mg protein) in fetus, newborn. and adult were 8 +/- 53, 15 0 +/- 18, and 357 +/- 21, respectively (P < 0.05). In normoxic MBC cer ebral arteries, the receptor density values in the three age groups we re 115 +/- 15, 105 +/- 9, and 99 +/- 5 fmol/mg protein, respectively. For fetal and adult Com, high-altitude, long-term hypoxemia was associ ated with decreases in Ins(1,4,5)P-3-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 decrease s in Ins(1,4,5)P-3-R density from control were 80 (to 23 +/- 3) and 47 % (to 53 +/- 7), respectively (P < 0.01). Ins(1,4,5)P-3 binding affini ty to the receptor averaged 11.8 +/- 0.5 nM and did not vary significa ntly as a function of vessel type, developmental age, or hypoxia. In C om, but not in MBC, Ins(1,4,5)P-3-R density increased dramatically wit h developmental age. This suggests that differences in Ins(1,4,5)P-3-R density values may account, in part, for differences in contractile r esponses of the two artery types in the several age groups. In respons e to long-term, high-altitude hypoxia, Ins(1,4,5)P-3-R density values in both fetal and adult Com and MBC decreased significantly, as did th eir NE-induced contraction. This suggests a cellular basis for changes in cerebrovascular contractility in response to longterm hypoxia and that Ins(1,4,5)P-3-R may play a role in acclimatization responses to h igh altitude.