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

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 α_1A-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 α_1D-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 α_1A-AR and α_1B-AR, but not α_1D-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 α_1D-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 α_1B-AR (CEC) and α_1D-AR (BMY-7378) inhibitors, but not by α_1A- AR inhibitors (5-MU or WB-4101). In conclusion, in the fetal CA, α_1B-AR and α_1D-AR subtypes play a key role in contractile response as well as in ERK activation. We speculate that in fetal CA α_1B-AR and α_1D-AR subtypes may be a critical factor associated with cerebrovascular growth and function.