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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043006-02
Application #
3361422
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Pelleg, A; Katchanov, G; Xu, J (1997) Autonomic neural control of cardiac function: modulation by adenosine and adenosine 5'-triphosphate. Am J Cardiol 79:11-4
Pelleg, A; Kutalek, S P (1997) Adenosine in the mammalian heart: nothing to get excited about. Trends Pharmacol Sci 18:236-8
Pelleg, A; Hurt, C M (1996) Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. J Physiol 490 ( Pt 1):265-75
Pelleg, A; Hurt, C M; Hewlett, E L (1996) ATP shortens atrial action potential duration in the dog: role of adenosine, the vagus nerve, and G protein. Can J Physiol Pharmacol 74:15-22
Xu, J; Pelleg, A (1996) A novel guinea pig heart model for studying AV nodal conduction and triggered activity in vivo. Am J Physiol 270:H1850-7
Katchanov, G; Xu, J; Hurt, C M et al. (1996) Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. III. Role of cardiac afferents. Am J Physiol 270:H1785-90
Xu, J; Hurt, C M; Pelleg, A (1995) Digoxin-induced ventricular arrhythmias in the guinea pig heart in vivo: evidence for a role of endogenous catecholamines in the genesis of delayed afterdepolarizations and triggered activity. Heart Vessels 10:119-27
Kollias-Baker, C; Xu, J; Pelleg, A et al. (1994) Novel approach for enhancing atrioventricular nodal conduction delay mediated by endogenous adenosine. Circ Res 75:972-80
Armour, J A; Huang, M H; Pelleg, A et al. (1994) Responsiveness of in situ canine nodose ganglion afferent neurones to epicardial mechanical or chemical stimuli. Cardiovasc Res 28:1218-25
Xu, J; Wang, L; Hurt, C M et al. (1994) Endogenous adenosine does not activate ATP-sensitive potassium channels in the hypoxic guinea pig ventricle in vivo. Circulation 89:1209-16

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