Subtype Specific Regulation of Human Vascular α 1 -Adrenergic Receptors by Vessel Bed and Age

Abstract

Background —α 1 -adrenergic receptors (α 1 ARs) regulate blood pressure, regional vascular resistance, and venous capacitance; the exact subtype (α 1a , α 1b , α 1 d ) mediating these effects is unknown and varies with species studied. In order to understand mechanisms underlying cardiovascular responses to acute stress and chronic catecholamine exposure (as seen with aging), we tested two hypotheses: (1) human α 1 AR subtype expression differs with vascular bed, and (2) age influences human vascular α 1 AR subtype expression. Methods and Results —Five hundred vessels from 384 patients were examined for α 1 AR subtype distribution at mRNA and protein levels (RNase protection assays, ligand binding, contraction assays). Overall vessel α 1 AR density is 16±2.3fmol/mg total protein. α 1a AR predominates in arteries at mRNA ( P <0.001) and protein ( P <0.05) levels; all 3 subtypes are present in veins. Furthermore, α 1 AR mRNA subtype expression varies with vessel bed (α 1a higher in splanchnic versus central arteries, P <0.05); competition analysis (selected vessels) and functional assays demonstrate α 1a and α 1b -mediated mammary artery contraction. Overall α 1 AR expression doubles with age (<55 versus ≥65 years) in mammary artery (no change in saphenous vein), accompanied by increased α 1b >α 1a expression ( P ≤0.001). Conclusions —Human vascular α 1 AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. These findings provide potential novel targets for therapeutic intervention in many clinical settings.