Characteristics of the beta-adrenergic receptor complex in the epicardial border zone of the 5-day infarcted canine heart
Steinberg, S.F.; Zhang, H.; Pak, E.; Pagnotta, G.; Boyden, P.A.
Circulation 91(11): 2824-2833
1995
ISSN/ISBN: 0009-7322 PMID: 7758190 Document Number: 443095
Background: The effect of isoproterenol on increasing the peak amplitude of the L-type calcium current is reduced in myocytes dispersed from the epicardial border zone (EBZ) of the 5-day infarcted canine heart when compared with control cells from noninfarcted hearts. This suggests that specific alterations in the beta-adrenergic receptor complex develop in this setting. The present study is an examination of individual components of the beta-adrenergic receptor complex with the aim of elucidating the biochemical defect(s) that might be responsible for the diminished beta-adrenergic receptor responsiveness in the myocytes that survive in the infarcted heart. Methods and Results: We compared components of the beta-adrenergic receptor signaling pathway in membranes prepared from the EBZ of the 5-day infarcted heart and a remote, noninfarcted region (RZ) of the same ventricle as well as the corresponding regions of noninfarcted ventricles. Defects in multiple components of the beta-adrenergic receptor complex were confined to the EBZ of the 5-day infarcted heart. These include a decrease in beta-adrenergic receptor density; diminished basal, guanine nucleotide-, isoproterenol-, forskolin-, and manganese-dependent adenylyl cyclase activities; an increase in the EC-50 for isoproterenol-dependent activation of adenylyl cyclase; a diminished level of the a-subunit of the G-s protein; and an elevated level of the alpha-subunit of the G-i protein. Conclusions: Defects in multiple components of the membrane beta-adrenergic receptor complex were identified in the EBZ of the 5-day infarcted canine heart. This constellation of abnormalities would be predicted to impair functional beta-adrenergic responsiveness and contribute to the defect in isoproterenol-dependent stimulation of the L-type calcium current in myoytes isolated from this tissue.