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

Abstract

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 alpha 1-adrenergic receptor (alpha 1-R) density (Bmax) or antagonist dissociation constant (KD), 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 alpha 1-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, alpha 1-R Bmax was 54 +/- 3, < 5 +/- 2, 23 +/- 3, and 35 +/- 3 fmol/mg protein, respectively. KD 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 microM. 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 alpha 1-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 alpha 1-R Bmax was much greater than in Com. These findings suggest important artery-to-artery differences in components of the cerebrovascular alpha 1-R-mediated contractile pathway. They also suggest considerable potential for modulation of pharmacomechanical coupling and homeostatic regulation of cerebrovascular tone.