Age-associated Changes in beta-Adrenergic Modulation on Rat Cardiac Excitation-Contraction Coupling

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Previous studies have demonstrated that the ability of beta-adrenergic receptor (betaAR) stimulation to increase cardiac contractility declines with aging. In the present study, the control mechanisms of excitation-contraction (EC) coupling, including calcium current (ICa), cytosolic Ca2+ (Ca2+i) transient and contraction in response to betaAR 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 Ca2+i transient did not differ markedly among cells from hearts of all age groups, the responses of the Ca (2+)i transient and contraction to beta-adrenergic stimulation by norepinephrine (NE) diminished with aging: the threshold concentration and the ED50 increased in rank order with aging; the maximum responses of contraction and Ca2+i transient decreased with aging. Furthermore, the efficacy of betaAR stimulation to increase ICa was significantly reduced with aging, and the diminished responses of the contraction and Ca (2+)i transient amplitudes to NE were proportional to the reductions in the ICa response. These findings suggest that the observed age-associated reduction in betaAR modulation of the cardiac contraction is, in part at least, due to a deficit in modulation of Ca2+i, particularly the activity of L-type calcium channels. (J. Clin. Invest. 1994. 94:2051-2059.) Key words: aging. beta-adrenergic receptor. calcium current. cytosolic calcium. contraction

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