PHARMACOLOGICAL ANALYSIS OF THE ACTIVITY OF THE ADENOSINE UPTAKE INHIBITOR, DIPYRIDAMOLE, ON THE SINOATRIAL AND ATRIOVENTRICULAR NODES OF THE GUINEA-PIG

1 Dipyridamole potentiates the effects of adenosine on the heart by in hibiting adenosine uptake. The effects of dipyridamole on both adenosi ne and N-ethylcarboxamidoadenosine (NECA) concentration-effect (E/[A]) curves were compared on the AV node, in guinea-pig isolated perfused hearts, and on the SA node, in isolated right atria, by measuring drom otropic and chronotropic responses, respectively. In the absence of di pyridamole, adenosine was significantly more potent on the AV node tha n SA node (AV p[A](50 )= 4.95 +/- 0.10, SA p[A](50 )= 3.62 +/- 0.10). In contrast, NECA and adenosine in the presence of dipyridamole were a pproximately equiactive in the two assays (NECA: AV p[A](50) = 7.07 +/ - 0.07; SA p[A](50 )= 7.30 +/- 0.08; adenosine: AV p[A](50 )= 6.49 +/- 0.08; SA p[A](50 )= 6.27 +/- 0.05). Dipyridamole was significantly mo re potent in enhancing the effects of adenosine on the SA node than on the AV node (pK(i) values estimated by Kenakin's method (1981): AV no de = 8.1 +/- 0.14; SA node = 8.75 +/- 0.08). 2 The difference in pK(i) values did not appear to be due to dipyridamole expressing other acti ons because concentrations of dipyridamole which saturated the adenosi ne transporter had no effect on the NECA E/[A] curves in either assay. However, the test of another assumption of Kenakin's method, that ade nosine taken up into cells is pharmacologically inactive, failed on th e AV node assay because a significant potentiating interaction was fou nd between adenosine and NECA. The interaction was concentration-depen dent, reciprocal to the extent that pre-incubation with either agonist potentiated the other and was concluded to be due to an intracellular action of adenosine as the potentiation disappeared in the presence o f dipyridamole. 3 An explanatory model was developed to account for th e data obtained using existing pharmacological concepts of ligand acti on in isolated tissue bioassays. In the model, adenosine, but not NECA , was assumed to be subject to saturable agonist uptake, an uptake whi ch was competitively blocked by dipyridamole. Adenosine and NECA were assumed to act extracellularly at adenosine A(1)-receptors. In the AV node, but not the SA node, the adenosine transported into the cells wa s assumed to potentiate the effects of adenosine A(1)-receptor activat ion. For the AV node assay, the model predicted that potentiation of a denosine by uptake blockade is offset by a simultaneous decrease in po tentiation due to the intracellular action of adenosine. All of the ex perimental data obtained in the study could be accounted for by the mo del including the apparent differences in potency of adenosine in the absence of dipyridamole and the pK(i) values for dipyridamole.