ALTERATIONS IN G-PROTEINS IN CONGESTIVE-HEART-FAILURE IN CARDIOMYOPATHIC (UM-X7.1) HAMSTERS

In order to explain the attenuated sympathetic support during the deve lopment of heart failure, the status of P-adrenergic mechanisms in the failing myocardium was assessed by employing cardiomyopathic hamsters (155-170 days old) at moderate degree of congestive heart failure. The norepinephrine turnover rate was increased but the norepinephrine con tent was decreased in cardiomyopathic hearts. The number and the affin ity of beta receptors in the sarcolemmal preparations were not changed in these hearts at moderate stage of congestive heart failure. While the basal adenylyl cyclase activity was not altered in sarcolemma, the stimulation of enzyme activity by NaF, forskolin, Gpp(NH)p or epineph rine was depressed in hearts from these cardiomyopathic hamsters. Sinc e G-proteins are involved in modifying the adenylyl cyclase activity, the functional and bioactivities as well as contents of both Gs and Gi proteins were determined in the cardiomyopathic heart sarcolemma. The functional stimulation of adenylyl cyclase by cholera toxin, which ac tivates Gs proteins, was markedly depressed whereas that by Pertussis toxin, which inhibits Gi proteins, was markedly augmented in cardiomyo pathic hearts. The cholera toxin and pertussis toxin catalyzed ADP-rib osylation was increased by 37 and 126%, respectively; this indicated i ncreased bioactivities of both Gs and Gi proteins in experimental prep arations. The immunoblot analysis suggested 74 and 124% increase in Gs and Gi contents in failing hearts, respectively. These results sugges t that depressed adenylyl cyclase activation in cardiomyopathic hamste rs may not only be due to increased content and bioactivity of Gi prot eins but the functional uncoupling of Gs proteins from the adenylyl cy clase enzyme may also be involved at this stage of heart failure.