AGE-ASSOCIATED CHANGES IN BETA-ADRENERGIC MODULATION ON RAT CARDIAC EXCITATION-CONTRACTION COUPLING

Previous studies have demonstrated that the ability of beta-adrenergic receptor (beta AR) stimulation to increase cardiac contractility declines with aging. In the present study, the control mechanisms of excitation-contraction (EC) coupling, including calcium current (I-Ca), cytosolic Ca2+ (Ca-i(2+)) transient and contraction in response to beta AR stimulation were investigated in ventricular myocytes isolated from rat hearts of a broad age range (2, 6-8, and 24 mo). While the baseline contractile performance and the Ca-i(2+) transient did not differ markedly among cells from hearts of all age groups, the responses of the Ca-i(2+) transient and contraction to beta-adrenergic stimulation by norepinephrine (NE) diminished with aging: the threshold concentration and the ED(50) increased in rank order with aging; the maximum responses of contraction and Ca-i(2+) transient decreased with aging. Furthermore, the efficacy of beta AR stimulation to increase I-Ca, was significantly reduced with aging, and the diminished responses of the contraction and Ca-i(2+) transient amplitudes to NE were proportional to the reductions in the I-Ca, response. These findings suggest that the observed age-associated reduction in beta AR modulation of the cardiac contraction is, in part at least, due to a deficit in modulation of Ca-i(2+), particularly the activity of L-type calcium channels.