Vol. 298, Issue 2, 531-538, August 2001

Contribution of Nitric Oxide and Prostanoids to the Cardiac Electrophysiological and Coronary Vasomotor Effects of Diadenosine Polyphosphates

Brigitte M. Stavrou, Desmond J. Sheridan and Nicholas A. Flores

Academic Cardiology Unit, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom

We investigated the hypothesis that the coronary vasomotor and cardiac electrophysiological effects of diadenosine polyphosphates (Ap_nA) are mediated via release of nitric oxide and prostanoids. Transmembrane right ventricular action potentials, refractory periods, and coronary perfusion pressure were recorded from isolated, Langendorff-perfused guinea pig hearts studied under constant flow conditions. The effects of threshold (1 nM) and maximal (1 µM) concentrations of diadenosine triphosphate (Ap₃A), tetraphosphate (Ap₄A), pentaphosphate (Ap₅A), and hexaphosphate (Ap₆A) were studied in the presence of nitric oxide (NO) synthase inhibitors [L-N^G-nitroarginine methyl ester, 300 µM; or L-N⁵-(1-iminoethyl)ornithine, 30 µM] or cyclooxygenase inhibitors (indomethacin, 100 µM or meclofenamate, 10 µM). Inhibition of cyclooxygenase and NO synthase both prevented the increases in action potential duration and refractory periods seen in response to Ap_nA. Cyclooxygenase inhibition altered the vasomotor effects of the Ap_nA in a manner that was related to the structure of the Ap_nA compound (the effects of Ap₃A were attenuated and those of Ap₄A and Ap₅A were prevented, while those of Ap₆A were not abolished.) Inhibition of NO synthase did not abolish the vasomotor responses. These results demonstrate the importance of nitric oxide and prostanoids in the cardiac responses to Ap_nA and support the hypotheses that the coronary vasomotor responses to Ap_nA are mediated via release of prostanoids, that this is related to the structure of the compound, and that the cardiac electrophysiological responses to Ap_nA involve both nitric oxide and prostanoid release.