CHARACTERISTICS OF THE BETA-ADRENERGIC-RECEPTOR COMPLEX IN THE EPICARDIAL BORDER ZONE OF THE 5-DAY INFARCTED CANINE HEART

Background The effect of isoproterenol on increasing the peak amplitud e of the L-type calcium current is reduced in myocytes dispersed from the epicardial border zone (EBZ) of the 5-day infarcted canine heart w hen compared with control cells from noninfarcted hearts. This suggest s that specific alterations in the beta-adrenergic receptor complex de velop in this setting. The present study is an examination of individu al components of the beta-adrenergic receptor complex with the aim of elucidating the biochemical defect(s) that might be responsible for th e diminished beta-adrenergic receptor responsiveness in the myocytes t hat survive in the infarcted heart. Methods and Results We compared co mponents of the beta-adrenergic receptor signaling pathway in membrane s prepared from the EBZ of the 5-day infarcted heart and a remote, non infarcted region (RZ) of the same ventricle as well as the correspondi ng regions of noninfarcted ventricles. Defects in multiple components of the beta-adrenergic receptor complex were confined to the EBZ of th e 5-day infarcted heart. These include a decrease in beta-adrenergic r eceptor density; diminished basal, guanine nucleotide, isoproterenol-, forskolin-, and manganese-dependent adenylyl cyclase activities; an i ncrease in the EC(50) for isoproterenol-dependent activation of adenyl yl cyclase; a diminished level of the alpha-subunit of the G(s) protei n; and an elevated level of the alpha-subunit of the G(i) protein. Con clusions Defects in multiple components of the membrane beta-adrenergi c receptor complex were identified in the EBZ of the 5-day infarcted c anine heart, This constellation of abnormalities would be predicted to impair functional beta-adrenergic responsiveness and contribute to th e defect in isoproterenol-dependent stimulation of the L-type calcium current in myocytes isolated from this tissue.