While an age-associated diminution in myocardial contractile response to β-adrenergic receptor (β-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern β-AR signaling must still be examined in aged hearts. Specifically, the contribution of β-AR subtypes (β1 versus β2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (G(i)) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished β-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both β1-AR and β2-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 β-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both β-AR subtypes and a reduction in membrane adenylyl cyclase response to both β-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either β1-AR or β2-AR stimulation were not rescued by inhibiting G(i) with pertussis toxin treatment. Further, the abundance or activity of β-adrenergic receptor kinase, GRK5, or G(i) did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both β1- and β2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both β-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor G, proteins appear to contribute to the age-associated reduction in cardiac β-AR responsiveness.
- Cardiac myocytes
- Inhibitory G proteins
- β-Adrenergic receptor kinase
- β-Adrenergic receptor subtype
ASJC Scopus subject areas