The present investigation aims to determine in vivo if nitric oxide (NO) is responsible for cytokine-induced myocardial depression. In vitro data indicates that the negative inotropic effect of cytokines on the heart are mediated by NO. In isolated hamster cardiac papillary muscle, this negative inotropic effect of cytokines can be blocked by N-G-monomethyl-L-arginine (NMA), an NO synthase inhibitor. Because the in vitro data show that NO synthase inhibitors prevented tumor necrosis factor (TNF)-induced myocardial depression of rapid onset and reversal, we studied low-dose recombinant human TNF challenge in canines. This TNF dose produces significant, early, and short-lived myocardial depression (resolved by 24 hours). We found that NMA did not prevent early (up to 6 hours) deleterious effects of TNF on cardiac function. In fact, during this period, TNF and NMA effects on all cardiac hemodynamic and metabolic parameters were additive (i.e., NMA did not block TNF effects). However, 24 hours 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 NO production. However, later, some deleterious effects of TNF may be related to production of NO. Given the finding suggestive of a beneficial effect of NMA at 24 h post TNF infusion, we are not evaluating the effect of NO inhibition in the setting of higher doses of TNF and longer lasting myocardial depression. Previous experiments using TNF challenges in canines suggest that this hypothesis is reasonable, i.e., there are two phases of cardiac injury. In canines, there is an early (<8 hour), dose-independent mechanism of myocardial depression and a late (>24 hour), dose- dependent mechanism of myocardial depression. Inhibition of NO may not be advantageous early when myocardial depression is dose dependent. We are now using TNF doses of 45 micrograms/kg and pretreating animals with doses of NMA of 40 mg/kg bolus followed by continuous infusion of 40 mg/kg/hour. We believe this investigation could provide information about the mechanism of the deleterious effects of TNF on cardiac function and could potentially provide the basis for the development of new therapeutic strategies for treating cardiovascular and hemodynamic derangements of sepsis. At present, cancer and MDS therapy with cytokines such as interleukin-2 is limited by cardiovascular depression. NMA is presently being used with cytokine therapies for cancer patients to inhibit their cardiovascular toxicities, and studies are planned in AIDS patients to do the same. These studies will also help determine the advisability of this approach.
