Pharmacological analysis of the activity of the adenosine uptake inhibitor, dipyridamole, on the sinoatrial and atrioventricular nodes of the guinea-pig

Abstract

1. Dipyridamole potentiates the effects of adenosine on the heart by inhibiting adenosine uptake. The effects of dipyridamole on both adenosine 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 dromotropic and chronotropic responses, respectively. In the absence of dipyridamole, adenosine was significantly more potent on the AV node than 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 approximately 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 more 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 node=8.18±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 actions because concentrations of dipyridamole which saturated the adenosine transporter had no effect on the NECA E/[A] curves in either assay. However, the test of another assumption of Kenakin's method, that adenosine taken up into cells is pharmacologically inactive, failed on the AV node assay because a significant potentiating interaction was found between adenosine and NECA. The interaction was concentration-dependent, 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 of dipyridamole.

3. An explanatory model was developed to account for the data obtained using existing pharmacological concepts of ligand action in isolated tissue bioassays. In the model, adenosine, but not NECA, was assumed to be subject to saturable agonist uptake, an uptake which was competitively blocked by dipyridamole. Adenosine and NECA were assumed to act extracellularly at adenosine A₁-receptors. In the AV node, but not the SA node, the adenosine transported into the cells was assumed to potentiate the effects of adenosine A₁-receptor activation. For the AV node assay, the model predicted that potentiation of adenosine by uptake blockade is offset by a simultaneous decrease in potentiation due to the intracellular action of adenosine. All of the experimental data obtained in the study could be accounted for by the model including the apparent differences in potency of adenosine in the absence of dipyridamole and the pK_i values for dipyridamole.

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