NITRIC OXIDE SYNTHASE INHIBITORS IN VIVO TNF-INDUCED MYOCARDIAL DEPRESSION

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The present investigation has been undertaken to determine, in vivo, if nitric oxide is responsible for cytokine-induced myocardial depress. The negative inotropic effect of cytokines on the heart are believed to be mediated by nitric oxide, based on in vitro data. In isolated hamster cardiac papillary muscle, this negative inotropic effect of cytokines can be blocked by N-G-monomethyl-L-arginine (NMA), a nitric oxide synthase inhibitor. Because the in vitro data shows that nitric oxide synthase inhibitors prevented TNF-induced myocardial depression of rapid onset and reversal, we studied a low dose of recombinant human TNF challenge in canines. This TNF dose produces significant, early and short lived myocardial depression (resolved by 24 h). Surprisingly, we found that NMA did not prevent the early (up to 6 h) deleterious effects of TNF on cardiac function. In fact, during this time period, TNF and NMA effects on all cardiac hemodynamic and metabolic parameters were additive (i.e. NMA did not block TNF effects). However, 24 h after TNF infusion, NMA did ameliorate the effects of TNF on some parameters such as acid base derangements and decreases in mean arterial pressure and systemic vascular resistance. These data suggest that the early phase of TNF-induced cardiac and other abnormalities may not be related to nitric oxide production. However, later, some deleterious effects of TNF may be related to production of nitric oxide. Given the finding suggestive of a beneficial effect of NMA at 24 h post TNF infusion, we are not evaluating the effect of nitric oxide inhibition in the setting of higher doses of TNF, and longer lasting myocardial depression. Previous experiments using TNF challenges in canines suggest that this is a reasonable hypothesis, i.e. two phases of cardiac injury. In canines, there is an early (<8h), dose independent mechanism of myocardial depression and a late (>24h), dose dependent mechanism of myocardial depression. It is possible that inhibition of nitric oxide is not advantageous early when myocardial depression is dose dependent. We are now using TNF doses of 45 microg /kg, and pretreating animals with doses of NMA of 40 mg/kg bolus followed by continuous infusion of 40 mg/kg/h. We believe that this investigation could provide information about the mechanism of the deleterious effects of TNF on cardiac function, could potentially provide the basis for the development of new therapeutic strategies for the treatment of cardiovascular depression. NMA is presently being used with cytokine therapies for cancer patients in order to inhibit their cardiovascular toxicities. These studies will also help determine the advisability of this approach.