NE-induced contraction, α₁-adrenergic receptors, and Ins(1,4,5)P₃ responses in cerebral arteries

Adrenergic-mediated responses in cerebral vessels in vitro differ with vessel segment. We performed this study to test the hypothesis that these vessel-specific cerebral artery norepinephrine (NE)-induced contractility changes are mediated in part by differences in α₁-adrenergic receptor (α₁-R) density (B(max)) or antagonist dissociation constant (K(D)), and/or inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] synthesis. In common carotid (Com), circle of Willis (Wil), and middle cerebral arteries (MCA) from adult sheep we measured NE-induced contractions. We also quantified α₁-R in these, and in anterior, middle, and posterior (AMP) cerebral arteries and cerebral microvessels (Micro). In addition, we quantified NE-induced Ins(1,4,5)P₃ synthesis. pD₂ values of Com and MCA were 5.2 ± 0.1 and 6.3 ± 0.1, respectively. In contrast, the MCA maximum response to NE compared with K⁺ was much lower than that of the Com. In the Com, Wil, AMP, and Micro, α₁-R B(max) was 54 ± 3, <5 ± 2, 23 ± 3, and 35 ± 3 fmol/mg protein, respectively. K(D) averaged 0.20 ± 0.05 nM in the several vessel groups. In Com and in AMP cerebral arteries, NE produced a rapid increase in Ins(1,4,5)P₃ with a peak at 45 s, and 50% effective concentration of 5.5 ± 0.2 μM. NE stimulated a 240% increase of Ins(1,4,5)P₃ in both Com and AMP, whereas Wil showed essentially no response. The ovine MCA was more sensitive to NE than was the Com. In contrast, MCA showed a much lower maximum contractile response to NE compared with K⁺. Cerebral arteries (AMP) had only about half the α₁-R density of the Com. In AMP cerebral arteries, both the basal and NE-stimulated Ins(1,4,5)P₃ values were much less than those of the Com. In MCA, the ratio of Ins(1,4,5)P₃ response to α₁-R B(max) was much greater than in Com. These findings suggest important artery-to-artery differences in components of the cerebrovascular α₁-R-mediated contractile pathway. They also suggest considerable potential for modulation of pharmacomechanical coupling and homeostatic regulation of cerebrovascular tone.