Bucindolol, a nonselective beta(1)- and beta(2)-adrenergic receptor antagonist, decreases beta-adrenergic receptor density in cultured embryonic chick cardiac myocyte membranes

Bucindolol and carvedilol, nonselective beta (1)- and beta (2)-adrenergic r eceptor antagonists, have been widely used in clinical therapeutic trials o f congestive heart failure. The aim of the current study was to investigate long-term effects of bucindolol or carvedilol on beta -adrenergic receptor protein and gene expression in cardiac myocytes. Embryonic chick cardiac m yocytes were cultured and incubated with bucindolol (1 muM), carvedilol (1 muM), or norepinephrine (1 muM) for 24 h. I-125-iodocyanopindolol binding a ssays demonstrated that incubation with norepinephrine or bucindolol, but n ot carvedilol, significantly decreased beta -adrenergic receptor density in crude membranes prepared from the myocytes. Neither bucindolol nor carvedi lol significantly stimulated adenylyl cyclase activity in membranes from dr ug untreated cells. Unlike by norepinephrine, the receptor density reductio n by bucindolol incubation was not accompanied by a change in beta (1)-adre nergic receptor messenger RNA abundance. A decrease in membrane beta -adren ergic receptor density without a change in cognate messenger RNA abundance was also observed in hamster DDT1 MF2 cell line incubated with bucindolol ( 1 muM, 24 h). We conclude that incubation with bucindolol, but not carvedil ol, results in true reduction of beta -adrenergic receptor density in chick cardiac myocyte membranes by mechanisms that are distinct from those respo nsible For receptor density reduction by the agonist norepinephrine.