Down regulation of myocardial beta 1-adrenoceptor signal transduction system in pacing-induced failure in dogs with aortic stenosis-induced left ventricular hypertrophy

We recently demonstrated that rapid ventricular pacing caused cardiac failu re (Failure) in dogs with aortic stenosis-induced left ventricular hypertro phy (Hypertrophy) and isoproterenol caused no significant increases in func tion, O-2 consumption and intracellular cyclic AMP level in the failing hyp ertrophied hearts. We tested the hypothesis that alterations in the beta(1) -adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during th e transition from the compensated hypertrophy to failure. Pressure overload -induced left ventricular hypertrophy was created using aortic valve plicat ion in 10 dogs over a 6-month period. Five months after aortic valve plicat ion, congestive heart failure was induced in 5 dogs by rapid ventricular pa cing at 240 bpm for 4 weeks. The density of myocardial beta(1)-adrenoceptor s (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduc ed in the Failure dogs (176 +/- 19; 755 +/- 136) when compared to those of the Control (344 +/- 51; 1,551 +/- 203) and the Hypertrophy (298 +/- 33; 1, 721 +/- 162) dogs. The receptor affinities were not significantly different among all groups. There was a small but significant decrease in the percen tage of beta(1)-adrenoceptors of the failing hypertrophied hearts (62 +/- 3 %) when compared to that of the hypertrophied hearts (77 +/- 5%). The basal myocardial adenylyl cyclase activity (rmoles/mg protein/min) was significa ntly lower in the Failure dogs (45 +/- 4) than in the Control (116 +/- 14) and Hypertrophy (86 +/- 6) dogs. The forskolin (0.1 mM)-stimulated adenylyl cyclase activity was also significantly lower in the Failure dogs (158 +/- 17) than in the Control dogs (296 +/- 35) and slightly lower than in the H ypertrophy dogs (215 +/- 10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude th at down regulation of beta(1)-adrenoceptors and reduced adenylyl cyclase ac tivities contribute to the decreases in myocardial functions and beta-adren ergic responses in the failing hypertrophied hearts induced by rapid ventri cular pacing.