Isolated Perfused Guinea Pig and Rat Hearts

Adenosine is known to cause atrioventricular block by slowing conduction through the atrioventricular node, thereby lengthening the atria to His (A-H) interval. To test the hypothesis that the increase in atrioventricular conduction delay produced by adenosine is mediated at an extracellular site, the efficacy of nucleoside transport inhibitors in preventing cellular adenosine uptake was correlated with their ability to potentiate the atrioventricular block and prolong the AH interval. The antagonism of aminophylline and adenosine also was examined. Since methylxanthines are known to inhibit cyclic nucleotide phosphodiesterase, to release catecholamines from nerve terminals, and to block adenosine receptors, it was determined whether the ability of aminophylline to reverse the adenosine-induced prolongation of the atrial-His interval and atrioventricular block was associated with an increase in myocardial cyclic AMP and/or release of norepinephrine. The atrial-His conduction time and adenosine uptake and release were determined in isolated perfused guinea pig and rat hearts. The nucleoside transport inhibitors dipyridamole, nitrobenzylthioinosine, and diazepam caused a dose-dependent decrease in the uptake of Cadenosine. Nitrobenzylthioinosine was the most and diazepam the least effective in blocking adenosine uptake. Dipyridamole (5 X 10~ M) inhibited uptake by 97% and increased adenosine levels in the perfusate. These effects were strongly correlated with a potentiation of adenosineinduced atrial-His prolongation (r = 0.99). The oligonucleotide, adenyl (3'-5')9-adenosine, an agent restricted to the extracellular space as a result of its large molecular size, was found to be 1.8 times more potent per mole than free adenosine. 2'-Deoxyadenosine and N-methyladenosine, respectively, were found to have either no effect or an effect similar to that of free adenosine on the atrial-His interval. Aminophylline (1 X 1CT to 3 X 10~ M) in the presence or absence of propranolol antagonized in a dose-dependent and competitive manner the prolongation of the atrial-His interval and atrioventricular block caused by adenosine. In concentrations up to 10~ M, aminophylline did not cause any accumulation of myocardial cyclic AMP, nor did it increase the release of norepinephrine. We conclude (1) that the effect of adenosine on atrioventricular conduction results from binding to an extracellular receptor that resembles the R site described for other actions of adenosine in different tissues, and (2) that the reversal of adenosine-induced increases in atrioventricular conduction delay by aminophylline is not due to phosphodiesterase inhibition and/or release of norepinephrine from nerve terminals. (Circ Res 51 -.569-579, 1982)