© 1995 American Heart Association, Inc.
Articles |
Effects of NO Modulation on Cardiac Arrhythmias in the Rat Isolated Heart
From the Cardiovascular Research Laboratories, Vascular Biology Research Centre, Department of Pharmacology, Division of Biomedical Sciences, King’s College, University of London (UK).
Abstract It has been proposed that NO may function as an endogenous cardioprotectant. We have investigated whether modulation of NO levels (detected in coronary effluent by chemiluminescence) by a blocker of its synthesis, by supplementation of its precursor, and by administration of an NO donor can influence reperfusion arrhythmias in the isolated rat heart. Rat hearts were perfused with modified Krebs’ solution and subjected to 5, 35, or 60 minutes of left regional ischemia followed by 10 minutes of reperfusion. NG-Nitro-L-arginine methyl ester (L-NAME), which blocks NO synthase, increased the incidence of reperfusion-induced ventricular fibrillation (VF) from 5% in the control condition to 35% after 60 minutes of ischemia (n=20, P<.05). The profibrillatory effect of L-NAME was prevented in hearts coperfused with 1 or 10 mmol/L L-arginine (an NO precursor) but persisted in hearts coperfused with D-arginine (1 mmol/L). L-NAME did not increase VF susceptibility in hearts reperfused after 5 or 35 minutes of ischemia. L-NAME caused sinus bradycardia (264±10 versus 309±5 bpm in control groups, P<.05) and reduced 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 effluent NO levels after 60 minutes of ischemia; during the first minute of reperfusion, values were reduced from 1457±422 to 812±228 pmol · min-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 similar changes occurred with other durations of ischemia, but the effects of L-NAME were not significant. L-NAME had no effect on QT interval; eg, values after 5 minutes of ischemia were 76±7 and 85±5 milliseconds in control and L-NAME–treated groups, respectively (n=20, P=NS). The NO donor sodium nitroprusside (10 µmol/L) significantly increased 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 1122±122 to 4093±1466 pmol · min-1 · g-1, P<.05). Sodium nitroprusside prevented the proarrhythmic effect of L-NAME and maintained coronary effluent NO levels during reperfusion. NO appears to function as an endogenous cardioprotectant antifibrillatory factor in rat heart during reperfusion following sustained ischemia.
Key Words: nitric oxide • reperfusion • ventricular fibrillation
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