Inositol 1,4,5-Trisphosphate Binding Sites in Aorta, Common Carotid, and Cerebral Arteries of Fetal, Newborn, and Adult Sheep. † 1345

Background. We and others have shown that adrenergic-mediated responses in cerebral vessels in vitro change with development, and differ with vessel segment. To test the hypothesis that these developmental and vessel specific cerebral artery contractility changes are mediated, in part, by changes in the inositol 1,4,5-trisphosphate-receptor (IP₃R) density or affinity, we performed the following study. Methods. In aorta (Ao), common carotid (COM), circle of Willis (WIL), and combined anterior, middle, and posterior (AMP) cerebral arteries from near-term fetal(≈140 d), newborn (3-5 d), and nonpregnant adult sheep, we quantified IP₃R with [³H]-IP₃ (4 to 6 assays per vessel group; p values given for both fetus and newborn vs adult). Results. In aorta, IP₃R density values (B_max in fmol/mg protein) for fetus, newborn, and adult, were 109±10, 118±32, and 181±18, respectively (p < 0.01). In the common carotid, these values were 85±3, 160±26, and 357±21, respectively (p < 0.05). The IP₃R density values for the circle of Willis in the three age groups were 52±6, 61±5, and 20±2, respectively (p < 0.01). In the cerebral arteries the B_max values in the age groups were 128±33, 113±16, and 99±5, respectively (ns). IP₃ binding affinity to the receptor (K_D) averaged 11.7±0.3 nM, and did not vary significantly as a function of either vessel type or developmental age. Conclusions. 1) In each age group there was a marked variation in IP₃R density among the several vessels. For adult and newborn sheep the density values were (COM > Ao > AMP > WIL). In contrast, the order for near-term fetus was AMP > Ao > COM > WIL. 2) Agonist binding affinity was not significantly different among the several vessel types or age groups. 3) These findings suggest that differences in IP₃R density values account, in part, for differences in contractile responses of the several arteries in the several age groups. (Of course, other elements of the cerebrovascular contractile pathway downstream may contribute to these differences). 4) These findings also suggest considerable potential for mechanisms of modulation of pharmaco-mechanical coupling and homeostatic regulation of cerebrovascular tone in the vessels of the several age groups.(Supported in part by USPHS Grant HD 03807)