ABSTRACT
Brief periods of myocardial ischemia and reperfusion render the myocardium tolerant to a subsequent sustained ischemia. This phenomenon has been known as ischemic preconditioning [PC]. It has recently become apparent that ischemic PC consists of two phases: an early phase, which occurs within minutes and disappears within 2 to 4 hours from the PC ischemia, and a late phase, which becomes manifest 24 hours later. The purpose of the present study was to test the hypothesis that the protective effect of ischemic PC is mediated by augmented nitric oxide [NO] formation. This study also aims at examining the effect of ischemic PC on postischemic myocardial tumor necrosis factor-alpha [TNF-alpha] production. This study was carried out on 38 healthy adult dogs of either sex. Six dogs were sacrificed and left ventricular myocardium was excised, homogenized and cardiac TNF-alpha homogenate was determined by chemiluminescence. Thirty-two dogs were randomized into 4 equal groups; Group I [preconditioned group], Group II [ischemic control group], Group III [preconditioned N-nitro-L-arginine methyl-ester [L-NA] treated group] and Group IV [ischemic L-NA treated group]. All groups were allowed 3 hours of reperfusion thereafter. Left ventricular systolic pressure [LVSP] and cardiac output [COP] were measured before and after left anterior descending coronary artery [LAD] occlusion reperfusion [O/R] in the four studied groups. After the three hours of reperfusion, TNF-alpha was measured in the cardiac homogenate of all groups. There was no statistically significant difference in LVSP and COP when comparing the four groups after LAD O/R However, there was a significant drop in both parameters in each of the four studied groups after LAD O/R. The absent short-term beneficial role of PC on myocardial contractility following O/R could be attributed to stunning of the myocardium: Furthermore, inhibition of NO synthesis did not attenuate myocardial stunning in preconditioned and ischemic anesthetized dogs. The present study also demonstrated that O/R increases cardiac TNF-alpha levels and that ischemic PC decreases ischemia-induced cardiac TNF-alpha production, which is still significantly higher in the preconditioned groups, compared with control group. This drop in myocardial TNF-alpha following ischemic PC did not improve postischemic functional recovery in anesthetized dogs. The absent short-term beneficial role of pretreatment with a NOS inhibitor could be explained by the fact that inducible NO synthase [iNOS] mediated only the late dysfunction induced by TNF-alpha