AGE-ASSOCIATED REDUCTIONS IN CARDIAC BETA(1)-ADRENERGIC AND BETA(2)-ADRENERGIC RESPONSES WITHOUT CHANGES IN INHIBITORY G-PROTEINS OR RECEPTOR KINASES

While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demo nstrated to occur in the context of increased levels of plasma catecho lamines, some critical mechanisms that govern beta-AR signaling must s till be examined in aged hearts, Specifically, the contribution of bet a-AR subtypes (beta(1) versus beta(2)) to the overall reduction in con tractile response with aging is unknown, Additionally, whether G prote in-coupled receptor kinases (GRKs), which mediate receptor desensitiza tion, or adenylyl cyclase inhibitory G proteins (G(i)) are increased w ith aging has not been examined, Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished beta-AR responsiveness and increased circulatory catechola mines. In this study, the contractile responses to both beta(1)-AR and beta(2)-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo), A marked age-associated depression in contractile response to both beta-AR subtype stimulation was obser ved, This was associated with a nonselective reduction in the density of both beta-AR subtypes and a reduction in membrane adenylyl cyclase response to both beta-AR subtype agonists, NaF or forskolin, However, the age-associated diminutions in contractile responses to either beta (1)-AR or beta(2)-AR stimulation were not rescued by inhibiting G(i) w ith pertussis toxin treatment, Further, the abundance or activity of b eta-adrenergic receptor kinase, GRK5, or G(i) did not significantly ch ange with aging. Thus, we conclude that the positive inotropic effects of both beta(1)- and beta(2)-AR stimulation are markedly decreased wi th aging in rat ventricular myocytes and this is accompanied by decrea ses in both beta-AR subtype densities and a reduction in membrane aden ylate cyclase activity, Neither GRKs nor G(i) proteins appear to contr ibute to the age-associated reduction in cardiac beta-AR responsivenes s.