OVEREXPRESSION OF MYOCARDIAL GS-ALPHA PREVENTS FULL EXPRESSION OF CATECHOLAMINE DESENSITIZATION DESPITE INCREASED BETA-ADRENERGIC-RECEPTOR KINASE

Inotropic and chronotropic responses to catecholamines in young adult transgenic mice overexpressing myocardial Gs alpha are enhanced. One m ight predict that over the life of the animal, this chronically enhanc ed beta-adrenergic receptor stimulation would result in homologous cat echolamine desensitization. To test this hypothesis, old transgenic Gs alpha mice and age-matched controls were studied physiologically in t erms of responsiveness of left ventricular function (ejection fraction ) to isoproterenol in vivo and in vitro in terms of beta-adrenergic re ceptor signaling. Old transgenic mice still responded to isoproterenol with augmented (P < 0.05) left ventricular ejection fraction (+44+/-3 %) compared with age-matched controls (+24+/-1%). Although total beta- adrenergic receptor density was reduced in the old transgenic mice, an d G protein receptor kinase 2 (beta-adrenergic receptor kinase) levels were increased, the fraction of receptors binding agonist with high a ffinity as well as isoproterenol- and G protein-stimulated adenylyl cy clase activities were enhanced. Thus, classical catecholamine desensit ization is not effective in attenuation of persistently enhanced respo nses to sympathetic stimulation in mice overexpressing myocardial Gs a lpha. To support this conclusion further, experiments were performed w ith chronic isoproterenol, which elicited effective desensitization in wild-type controls, but failed to elicit desensitization in overexpre ssed Gs alpha mice. The results of this study suggest that the lack of protective desensitization mechanisms may be responsible in part for the dilated cardiomyopathy which develops with chronic sympathetic str ess over the life of these animals.