α1-adrenergic receptor subtype function in fetal and adult cerebral arteries

Abstract

In the developing fetus, cerebral artery (CA) contractility demonstrates significant functional differences from that of the adult. This may be a consequence of differential activities of α1-adrenergic receptor (α1-AR) subtypes. Thus we tested the hypothesis that maturational differences in adrenergic-mediated CA contractility are, in part, a consequence of differential expression and/or activities of α1-AR subtypes. In CA from fetal (∼140 days) and nonpregnant adult sheep, we used wire myography and imaging, with simultaneous measurement of tension and intracellular Ca2+ concentration ([Ca 2+]i), radioimmunoassay, and Western immunoblots to examine phenylephrine (Phe)-induced contractile responses. The α1A-AR antagonists (5-MU and WB-4101) completely inhibited Phe-induced contraction in adult but not fetal CA; however, [Ca2+]i increase was reduced significantly in both age groups. The α1D-AR antagonist (BMY-7378) blocked both Phe-induced contractions and Ca2+ responses to a significantly greater extent in adult compared with fetal CA. In both age groups, inhibition of α1A-AR and α1B-AR, but not α1D-AR, significantly reduced inositol 1,4,5-trisphosphate responses to Phe. Western immunoblots demonstrated that the α1- AR subtype expression was only ∼20% in fetal CA compared with the adult. Moreover, in fetal CA, the α1D-AR was expressed significantly greater than the other two subtypes. Also, in fetal but not adult CA, Phe induced a significant increase in activated ERK1/2; this increase in phosphorylated ERK was blocked by α1B-AR (CEC) and α1D-AR (BMY-7378) inhibitors, but not by α1A- AR inhibitors (5-MU or WB-4101). In conclusion, in the fetal CA, α1B-AR and α1D-AR subtypes play a key role in contractile response as well as in ERK activation. We speculate that in fetal CA α1B-AR and α1D-AR subtypes may be a critical factor associated with cerebrovascular growth and function. Copyright © 2010 the American Physiological Society.