Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age

Background-alpha(1)-adrenergic receptors (alpha(1)ARs) regulate blood press ure, regional vascular resistance, and venous capacitance: the exact subtyp e (alpha(1a), alpha(1b), alpha(1d)) mediating these effects is unknown and varies with species studied. In order to understand mechanisms underlying c ardiovascular responses to acute stress and chronic catecholamine exposure las seen with aging), we tested two hypotheses: (1) human alpha(1)AR subtyp e expression differs with vascular bed, and (2) age influences human vascul ar alpha(1)AR subtype expression. Methods and Results-Five hundred vessels from 384 patients were examined fo r alpha(1)AR subtype distribution at mRNA and protein levels (RNase protect ion assays, ligand binding, contraction assays). Overall vessel alpha(1)AR density is 16 +/- 2.3 fmol/mg total protein. alpha(1a)AR predominates in ar teries at mRNA (P < 0.001) and protein (P < 0.05) levels; all 3 subtypes ar e present in veins. Furthermore, (alpha(1)AR mRNA subtype expression varies with vessel bed (alpha(1a) higher in splanchnic versus central arteries, P < 0.05); competition analysis (selected vessels) and functional assays dem onstrate alpha(1a) and alpha(1b)-mediated mammary artery contraction. Overa ll alpha(1)AR expression doubles with age (<55 versus greater than or equal to 65 years) in mammary artery (no change in saphenous vein), accompanied by increased alpha(1b)>alpha(1a) expression (P less than or equal to 0.001) . Conclusions-Human vascular alpha(1)AR subtype distribution differs from ani mal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. These findings provide potential novel t argets for therapeutic intervention in many clinical settings.