Human aging is associated with several significant alterations in cardiac function that are deleterious. The incidence of sinus node dysfunction increases with age, and the chronotropic response to exercise is impaired in healthy elderly persons. Data from isolated cardiac muscle of senescent rats reveal a prolonged duration of contraction and relaxation when compared to younger animals. Theophylline is a widely-used bronchodilator drug with significant cardiac effects, including increased heart rate and contractility. These effects may be mediated by several mechanisms: stimulation of the sympathetic nervous system, inhibition of cAMP phosphodiesterase, antagonism of the binding of extracellular adenosine at cell-surface receptors, or direct effects on the availability of intracellular calcium. Based on our preliminary studies that show an increased inotropic response to intravenous theophylline in healthy elderly men compared with healthy young men, we propose further studies to investigate the hypothesis that the inotropic response to acute theophylline administration is greater in elderly than in younger adults. We have preliminary evidence that the difference is not due to sympathetic nervous system activation. Therefore, autonomic blockade should not attenuate this age-related effect. However, chronic theophylline administration may result in similar cardiac effects among different age groups in the absence of sympathetic nervous system activation, possibly due to up-regulation of adenosine receptors. The objectives of this study are: (1) to derive age-adjusted calculations for systolic time intervals as a noninvasive measure of the inotropic state of the heart; (2) to determine the age-related inotropic effect of acute theophylline administration; (3) to determine the cardiac effects of chronic oral theophylline administration; and (4) to determine if the age-related differences of acute and chronic theophylline administration on cardiac function are due to sympathetic nervous system stimulation. The results of the proposed research will increase our understanding of the pharmacology of the aging heart and may lead to new therapeutic approaches for the management of cardiac disease in elderly patients.
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| Kapicka, C L; Montamat, S C; Mudumbi, R V et al. (2000) Effects of cyclopentyladenosine on isoproterenol response in adult and senescent cardiac tissue from Fischer 344 rats. J Pharmacol Exp Ther 293:599-606 |
