Abstract
We investigated the hypothesis that the coronary vasomotor and cardiac electrophysiological effects of diadenosine polyphosphates (ApnA) 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-NG-nitroarginine methyl ester, 300 μM; orl-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 ApnA. Cyclooxygenase inhibition altered the vasomotor effects of the ApnA in a manner that was related to the structure of the ApnA 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 ApnA and support the hypotheses that the coronary vasomotor responses to ApnA are mediated via release of prostanoids, that this is related to the structure of the compound, and that the cardiac electrophysiological responses to ApnA involve both nitric oxide and prostanoid release.
Footnotes
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Supported by British Heart Foundation Project Grant PG 98/102.
- Abbreviations:
- ApnA
- diadenosine polyphosphates
- Ap3A
- diadenosine triphosphate
- Ap4A
- diadenosine tetraphosphate
- Ap5A
- diadenosine pentaphosphate
- Ap6A
- diadenosine hexaphosphate
- l-NAME
- l-NG-nitroarginine methyl ester
- l-NIO
- l-N5-(1-iminoethyl)ornithine
- APD95
- action potential duration at 95% repolarization
- RP
- refractory period
- KATP
- ATP-dependent potassium channel
- EDHF
- endothelium-derived hyperpolarizing factor
- NO
- nitric oxide
- PGI2
- prostacyclin
- Received January 24, 2001.
- Accepted April 13, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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