Intrapericardial Delivery of l -Arginine Reduces the Increased Severity of Ventricular Arrhythmias During Sympathetic Stimulation in Dogs With Acute Coronary Occlusion

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Abstract
Background Nitric oxide (NO) modulates autonomic effects on myocardial contractility and sinus and atrioventricular nodal function of the heart. Whether NO influences autonomic actions on ventricular electrophysiological properties and arrhythmogenesis is not known. Methods and Results Four groups consisting of 43 autonomically denervated dogs were studied. To “superfuse” sympathetic nerves innervating the ventricles, test drugs were introduced into the pericardial sac for 30 minutes, and their effects on ventricular effective refractory period (ERP) and arrhythmia development were assessed before and during sympathetic stimulation (SS). In group 1 (n=12), ventricular ERPs showed no significant difference between control and superfusion with l-arginine, a NO precursor (222±20 versus 222±19 ms, P=.485). However, l-arginine significantly reduced SS-induced ERP shortening compared with control (9±7 versus 13±7 ms, P<.001). Simultaneous administration of NG-monomethyl-l-arginine (2 mg/mL) abolished the inhibitory effects of l-arginine (13±7 versus 13±7 ms, P=.885). In group 2 (n=15), the severity of ventricular arrhythmias significantly increased during SS. l-Arginine reduced this increase caused by SS. In group 3 (n=8), plasma norepinephrine spillover measured from the coronary sinus significantly increased during SS and was reduced by pericardial superfusion with l-arginine compared with control (6005.2±1525.6 versus 8503.4±2044.5 pg/min, P=.012). In group 4 (n=8), l-arginine pericardial superfusion significantly increased NO overflow measured from the coronary sinus during SS (93.25±59.20 versus 114.82±74.92 nmol/min, P=.043). Conclusions Pericardial l-arginine reduces ERP shortening and increased severity of ischemic ventricular arrhythmias during SS in dogs. NO-induced reduction of norepinephrine release in the heart may be one of the underlying mechanisms.