Down regulation of myocardial beta1-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 failure (Failure) in dogs with aortic stenosis-induced left ventricular hypertrophy (Hypertrophy) and isoproterenol caused no significant increases in function, O2 consumption and intracellular cyclic AMP level in the failing hypertrophied hearts. We tested the hypothesis that alterations in the beta1-adrenoceptor-signal transduction pathway would correlate with the reduced functional and metabolic responses to beta-adrenergic stimulation during the transition from the compensated hypertrophy to failure. Pressure overload-induced left ventricular hypertrophy was created using aortic valve plication in 10 dogs over a 6-month period. Five months after aortic valve plication, congestive heart failure was induced in 5 dogs by rapid ventricular pacing at 240 bpm for 4 weeks. The density of myocardial beta1-adrenoceptors (fmoles/mg membrane protein; fmoles/g wet tissue) was significantly reduced 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 percentage of beta1-adrenoceptors of the failing hypertrophied hearts (62+/-3%) when compared to that of the hypertrophied hearts (77+/-5%). The basal myocardial adenylyl cyclase activity (pmoles/mg protein/min) was significantly 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 Hypertrophy dogs (215+/-10). There were no significant differences in low Km cyclic AMP-phosphodiesterase activities among all groups. We conclude that down regulation of beta1-adrenoceptors and reduced adenylyl cyclase activities contribute to the decreases in myocardial functions and beta-adrenergic responses in the failing hypertrophied hearts induced by rapid ventricular pacing.