Preconditioning of Ischemic Myocardium via Involvement of the L-arginine/Nitric Oxide Synthase Pathway
The objective of this investigation was to evaluate involvement of the L-arginine/ nitric oxide synthase pathway in myocardial ischemic preconditioning as assessed by myocardial infarct size. Using New Zealand White rabbits, the nitric oxide precursor, L-arginine, was administered alone or in conjunction with the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). These animals were compared to ones treated with the saline vehicle, D-arginine, or L-NAME only. Systemic hemodynamics, including heart rate, arterial and left ventricular pressures, and myocardial contractility (LV +dp/dt max) were monitored throughout each experiment. A branch of the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion. The saline vehicle, D-arginine, or L-arginine were administered as 5 min intraventricular infusions, followed by 10 min of recovery period prior to the sustained occlusion. Intravenous administration of L-NAME was carried out for 90 min prior to brief intraventricular infusion of either the saline vehicle or L-arginine. Systemic hemodynamics were not significantly different from control in most cases, except for the development of a moderate depression of heart rate, mean arterial pressure, and myocardial contractility which occurred in both treatment groups receiving L-NAME. A modest though significant myocardial contractile depression was noted in the L-arginine group, while a transient increase of left ventricular end diastolic pressure was observed in the saline vehicle group. Myocardial area at risk was not significantly different among treatment groups. Brief infusion of exogenous L-arginine to simulate preconditioning significantly reduced infarct size below the saline vehicle treatment group This cardioprotective effect of L-arginine was abolished as a result of administration of L-NAME prior to L-arginine infusion. Neither D-arginine nor L-NAME only infusions significantly altered the degree of infarction compared to the saline vehicle group. Thus, these results suggest the L-arginine/NO pathway may be a physiological mediator of the endogenous protective mechanisms involved in myocardial preconditioning. However, further investigations are necessary to determine the exact involvement of this pathway in ischemic preconditioning.
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