EFFECTS OF NO MODULATION ON CARDIAC-ARRHYTHMIAS IN THE RAT ISOLATED HEART

It has been proposed that NO may function as an endogenous cardioprote ctant. We have investigated whether modulation of NO levels (detected in coronary effluent by chemiluminescence) by a blocker of its synthes is, by supplementation of its precursor, and by administration of an N O donor can influence reperfusion arrhythmias in the isolated rat hear t. Rat hearts were perfused with modified Krebs' solution and subjecte d to 5, 35, or 60 minutes of left regional ischemia followed by 10 min utes of reperfusion. N-G-Nitro-L-arginine methyl ester (L-NAME), which blocks NO synthase, increased the incidence of reperfusion-induced ve ntricular fibrillation (VF) from 5% in the control condition to 35% af ter 60 minutes of ischemia (n=20, P<.05). The profibrillatory effect o f L-NAME was prevented in hearts coperfused with 1 or 10 mmol/L L-argi nine (an NO precursor) but persisted in hearts coperfused with D-argin ine (1 mmol/L). L-NAME did not increase VF susceptibility in hearts re perfused after 5 or 35 minutes of ischemia. L-NAME caused sinus bradyc ardia (264+/-10 versus 309+/-5 bpm in control groups, P<.05) and reduc ed coronary flow before ischemia (6.2+/-0.6 versus 9.2+/-0.6 mL . min( -1). g(-1) tissue in controls, P<.05). L-NAME reduced coronary effluen t NO levels after 60 minutes of ischemia; during the first minute of r eperfusion, values were reduced from 1457+/-422 to 812+/-228 pmol . mi n(-1). g(-1) (P<.05). This effect was prevented by coperfusion with L- arginine (10 344+/-1730 pmol . min(-1). g(-1), P<.05). Qualitatively s imilar changes occurred with other durations of ischemia, but the effe cts of L-NAME were not significant. L-NAME had no effect on QT interva l; eg, values after 5 minutes of ischemia were 76+/-7 and 85+/-5 milli seconds in control and L-NAME-treated groups, respectively (n=20, P=NS ). The NO donor sodium nitroprusside (10 mu mol/L) significantly incre ased coronary flow 1 minute before ischemia (15.4+/-1.1 versus 9.2+/-0 .6 mL . min(-1). g(-1) tissue and coronary effluent NO levels (from 11 22+/-122 to 4093+/-1466 pmol . min(-1). g(-1), P<.05). Sodium nitropru sside prevented the proarrhythmic effect of L-NAME and maintained coro nary effluent NO levels during reperfusion. NO appears to function as an endogenous cardioprotectant antifibrillatory factor in rat heart du ring reperfusion following sustained ischemia.