Differential role of α1‐adrenergic receptor subtypes in Ca2+‐dependent and Ca2+‐independent contraction in developing cerebral arteries

Abstract

ObjectiveCerebral arteries in the fetus differ functionally from adult. We tested the hypothesis that developmental differences are a consequence of differential activities of α1‐adrenergic receptor (α1‐AR) subtypes.MethodsIn middle cerebral arteries from fetal and adult sheep, we measured responses of Ins(1,4,5)P3, vascular tension, and [Ca2+]i to the α1‐AR agonist phenylephrine (PHE, 10−5 M), in presence of blockers.ResultsIn fetal cerebral arteries, expression levels of each α1‐AR subtype was only ~20% that of adult. In fetus, each subtype specific blocker, 5‐MU (α1A), CEC (α1B) and BMY‐7378 (α1D) inhibited to a degree greater degree PHE‐induced tension and [Ca2+]i, compared to adult. Although in arteries of both age groups, 5‐MU and CEC reduced Ins(1,4,5)P3 responses to PHE ~35%, BMY‐7378 showed no significant decrease in Ins(1,4,5)P3 responses. Also in fetal arteries, the PHE‐induced increase in activated ERKs was blocked by CEC and BMY‐7378, but not by 5‐MU or WB‐4101.ConclusionsIn both age groups α1A‐ and α1B‐AR appear to mediate α1‐adrenergic‐Ins(1,4,5)P3 responses. In the fetus in contrast, α1D‐AR appear to activate the MAPK/ERK1/2 cascade by non‐Ins(1,4,5)P3‐dependent mechanisms. In the immature organism, relative deficiency of specific α1‐AR subtypes, and their differing signaling pathways, may be critical factors associated with dysregulation of cerebral blood flow. (USPHS HD 03708)