Contribution of nitric oxide and prostanoids to the cardiac electrophysiological and coronary vasomotor effects of diadenosine polyphosphates

We investigated the hypothesis that the coronary vasomotor and cardiac elec trophysiological effects of diadenosine polyphosphates (AP(n)A) are mediate d via release of nitric oxide and prostanoids. Transmembrane right ventricu lar 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 maxima l (1 muM) concentrations of diadenosine triphosphate (Ap(3)A), tetraphospha te (Ap(4)A), pentaphosphate (Ap(5)A), and hexaphosphate (Ap(6)A) were studi ed in the presence of nitric oxide (NO) synthase inhibitors [L-N-G-nitroarg inine methyl ester, 300 muM; or L-N-5-(1-iminoethyl)ornithine, 30 muM] or c yclooxygenase inhibitors (indomethacin, 100 muM or meclofenamate, 10 muM). Inhibition of cyclooxygenase and NO synthase both prevented the increases i n action potential duration and refractory periods seen in response to Ap(n )A. Cyclooxygenase inhibition altered the vasomotor effects of the Ap(n)A i n a manner that was related to the structure of the Ap(n)A compound (the ef fects of Ap(3)A were attenuated and those of Ap(4)A and Ap(5)A were prevent ed, while those of Ap(6)A were not abolished.) Inhibition of NO synthase di d not abolish the vasomotor responses. These results demonstrate the import ance of nitric oxide and prostanoids in the cardiac responses to Ap(n)A and support the hypotheses that the coronary vasomotor responses to Ap(n)A are mediated via release of prostanoids, that this is related to the structure of the compound, and that the cardiac electrophysiological responses to Ap (n)A involve both nitric oxide and prostanoid release.