The study is designed to determine the physiologic and pathophysiologic importance of adenosine in the control of heart rate. It will examine the negative chronotropic effect of exogenous and endogenous adenosine on the sinoatrial node, the physiological cardiac pacemaker, both in intact animals with chronic cardiovascular instrumentation and in isolated sinoatrial node preparations. In addition to measuring the final effect on heart rate, the experiments will examine the electrophysiological effects of adenosine on the resting membrane and action potentials of single SA node cells in situ and also the possibility of adenosine-induced shifts in the pacemaker locus to sites outside the sinoatrial node. The membrane receptors responsible for adenosine's sinoatrial action will be cahracterized by measuring the ralative potencies of a series of structural adenosine analogues in terms of their physiological and biochemical effects. The role of cyclic nucleotides in mediating adenosine's negative chronotropic effect will be determined using cyclic nucleotide measurements and pharmacological probes. Interaction between adenosine and cholinergic control of heart rate will be defined. Finally, by use of pharmacological modulators of adenosine's action and also measurements of adenosine levels, the importance of endogenous adenosine in the bradycardia responses to hypoxia and focal ischemia and in certain bradyarhythmias secondary to myocardial hypertrophy and dilatation will be determined. The study will contribute to our basic understanding of heart rate control and will also contribute to a better understanding of the etiology and possible treatment of certain cardiac arrhythmias found in man.
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