Alterations in activities of cyclic nucleotide systems and in β-adrenergic receptor-mediated activation of cyclic amp-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy

Initial and transient increases in the basal levels of cyclic GMP in the heart were noted prior to cardiac hypertrophy in rats administered isoprotenol. Increased levels of cyclic AMP-phosphodiesterase (in both the soluble and particulate fractions) and stimulatory modulator of cyclic GMP-dependent protein kinase, however, were associated with the progression, or the state, of cardiomegaly, with their levels returning to the control values upon regression of the hypertrophy. The levels of cyclic GMP phosphodiesterase in the soluble fraction were lower, whereas those in the particulate fraction were higher, in the hypertrophied heart than the control. In cardiac hypertrophy, the maximal activity ratio (-cyclic AMP/+cyclic AMP) of cyclic AMP-dependent protein kinase in the incubated minced heart caused by isoproterenol was lower, whereas the concentration of isoproterenol required to increase the activit ratio half-maximally was higher than controls; The reduced responsiveness to the drug, however, was reversed when the hypertrophy regressed. These observations, taken collectively, appear to suggest that the desensitization of the β-adrenergic mechanism seen in the cardiac hypertrophy produced by repeated administration of isoproterenol is associated with adaptive modifications in certain parameters of the cyclic nucleotide systems.