Adenosine, released from myocardial cells myocardial ischemia and catecholamine stimulation is a physiological modulator of the cardiovascular system. It effects, mediated by specific receptors, are due to a direct action on the membrane and an indirect, anti-adrenergic, action. Recently, adenosine had been viewed as a biological cardioprotective agent which plays an important role in pathophysiologic conditions. However, the mechanisms of adenosine's actions in vivo are not fully known. In particular, little is known regarding mechanisms of adenosine's effects on cardiac electrophysiology, arrhythmogenesis and inotropism. Furthermore, the ability of adenosine to antagonize the effects of catecholamines in vivo is highly controversial. Thus, the proposed studies are aimed to characterize the cardiac electrophysiologic and inotropic effects of adenosine in vivo and to determine the mechanistic role of the indirect anti-adrenergic action in these effects. For this purpose several canine models already established in our laboratory will be used. These include, (a) chronic AV conduction block and ventricular escape rhythm, enabling the comparative simultaneous evaluation of adenosine actions on the sinus node and ventricular pacemakers, (b) femoral artery to left anterior descending coronary artery shunt, enabling localized perturbations and intramyocardial pressure determination, and (c) femoral to anterior septal artery tachycardias. Using these models the following quantitative data will be obtained: 1. The negative chronotropic and dromotropic effects of adenosine in normal myocardium; 2. The differential sensitivity of cardiac pacemakers to adenosine; 3. The effects of adenosine on the electrophysiologic and inotropic actions catecholamines; and 4. The effects of adenosine on non-reentrant ventricular arrhythmias. Specially, the administration of catecholamine, adrenergic receptor blocker, adenosine antagonists, adenosine deaminase inhibitors and adenosine transport inhibitors in norma, ischemic and autonomically perturbed animals will be used to determine the mechanism of the actions of adenosine in vivo. Furthermore studies with competitive receptor-selective adenosine inhibitors and agents which modulate specific adenosine receptors and G- proteins in adenosine's actions. The proposed studies will systematically elucidate the basic mechanisms of the electrophysiologic, inotropic and anti-adrenergic actions of adenosine in a series of well defined experimental conditions in vivo and will characterize its role as a biological cardioprotective agent. This information is critical to the ultimate clinical application cardioprotective agents which depend on the action of adenosine for their modulating effects.
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