NITRIC-OXIDE AND PROSTACYCLIN MODULATE THE ALTERATIONS IN CARDIAC ACTION-POTENTIAL DURATION MEDIATED BY PLATELETS DURING ISCHEMIA

Objective: To investigate the effects of alterations of nitric oxide ( NO) and prostacyclin (PGI,) availability on platelet-mediated electrop hysiological effects during myocardial ischaemia. Methods: Transmembra ne action potentials and electrograms were recorded from isolated, Lan gendorff-perfused guinea-pig hearts during normal perfusion, global my ocardial ischaemia and reperfusion during infusion of washed human pla telets. Experiments were performed in the presence of 100 mu M N-G-nit ro-L-arginine methyl ester (L-NAME), 30 mu M L-arginine, 10 mu M haemo globin, 100 mu M sodium nitroprusside and 2.3 nM iloprost, or using he arts obtained from DL-lysine monoacetylsalicylate (Aspisol(R), 50 mg . kg(-1) i.p.)-treated animals. Results: Perfusion with L-NAME and haem oglobin increased perfusion pressure by 33% (P = 0.0017) and 23% (P = 0.0026) while sodium nitroprusside and iloprost reduced it (17%, P = 0 .0004, and 24%, P = 0.0006). In the absence of platelets, these compou nds had no effect on arrhythmogenesis, but in the presence of platelet s L-NAME reduced the onset time of ventricular tachycardia during isch aemia from 19.4 (s.e.m. 2.0) min to 12.9 (2.1) min, P = 0.04 and accen tuated the ischaemia-induced reduction of action potential duration at 95% repolarization (APD(95)): 95(6) vs. 115(5) ms, P < 0.05 at 25 min . Sodium nitroprusside in the presence of platelets attenuated the isc haemia-induced reduction in APD(95), while iloprost in the presence of platelets was antiarrhythmic (ventricular fibrillation 25 vs. 75%, P = 0.04) and attenuated the reduction in APD(95) during ischaemia 115(4 ) vs. 94(4) ms, P <0.05 at 20 min. Infusion of platelets into hearts o btained from DL-lysine-monoacetylsalicylate-treated guinea-pigs accent uated the ischaemia-induced reduction in APD(95) (94(4) vs. 119(7) ms, P < 0.05 at 20 min) and this was reversed by sodium nitroprusside (11 7(7) ms, P < 0.05 at 20 min). L-NAME and haemoglobin had no effect on the aggregatory responses of the platelets to 5 mu M ADP and 4 mu g . ml(-1) collagen, while sodium nitroprusside and iloprost ablated the r esponses to ADP and reduced the responses to collagen (maximum height of the aggregatory response reduced by 75 and 84%, respectively, both P = 0.03.) Conclusions: Inhibition of NO and PGI(2) synthesis exacerba tes the reduction in cardiac action potential duration associated with platelet activation during ischaemia, while provision of exogenous NO and PGI(2) attenuates the reduction in cardiac action potential durat ion. Provision of exogenous NO and PGI(2) (as iloprost) was associated with inhibition of platelet reactivity.