Developmental changes in α₁-adrenergic receptors, IP₃ responses, and NE-induced contraction in cerebral arteries

Cerebral arteries show significant developmental and artery-specific changes in noradrenergic-mediated contraction. To test the hypothesis that these changes result from differences in the density of α₁-adrenergic receptors (α₁-ARs) and/or norepinephrine (NE)induced inositol 1,4,5- trisphosphate [Ins(1,4,5)P₃,IP₃] synthesis, we quantified these variables and the NE-induced contraction in the common carotid artery (Com) and main branch cerebral arteries (MBC) from term fetal (~140 gestational day) and newborn (2- to 5-day) sheep and compared them with adult values. In fetal and newborn Com, maximal contractions to NE (percent K⁺ maximum response) were 132 ± 14 and 118 ± 9%, respectively (adult = 92 ± 7%). For fetal and newborn middle cerebral artery, these values were 34 ± 10 and 43 ± 7%, respectively (adult = 24 ± 7%). α₁-AR density values in Com of fetal and newborn sheep were 113 ± 18 and 106 ± 4 fmol/mg protein, respectively (adult = 54 ± 3 fmol/mg protein). For the MBC, density values were 47 ± 2 and 24 ± 3 fmol/mg protein, respectively (adult = 23 ± 3 fmol/protein). In term fetal and newborn MBC, NE produced dose-dependent increases in Ins(1,4,5)P₃, the maximal increases above basal values being 245 ± 40 and 189 ± 16%, respectively (adult = 254 ± 35%). Neither fetus nor newborn Com showed significant Ins(1,4,5)P₃ responses to NE. We concluded that in fetal and newborn Com and MBC, α₁-AR density and NE-induced Ins(1,4,5)P₃ response varied as a function of developmental age and specific vessel. However, these variations did not correlate with NE-induced maximum contraction. Thus we reject the hypothesis that age-dependent and vessel- specific differences of cerebral artery adrenergic-mediated contraction are a function of α₁-AR density or Ins(1,4,5)P₃ response. Rather, the differences would appear to result from other factors such as non- Ins(1,4,5)P₃-mediated calcium activation and/or sensitivity to Ins(1,4,5)P₃. The studies also suggest considerable potential for maturational modulation of pharmacomechanical coupling and homeostatic regulation of cerebrovascular tone.