N-G-METHYL-L-ARGININE, AN INHIBITOR OF NITRIC-OXIDE FORMATION, ACTS SYNERGISTICALLY WITH DOBUTAMINE TO IMPROVE CARDIOVASCULAR PERFORMANCE IN ENDOTOXEMIC DOGS

Objective: To evaluate the hemodynamic effects of the nitric oxide inh ibitor, N-G-methyl-L-arginine, and dobutamine during experimental endo toxemia. Design: Prospective, randomized, controlled animal study. Set ting: University research laboratory. Subjects: Adult, male mongrel do gs. Interventions: After catheterization with a flow-directed, thermal -dilution puhnonary artery flotation catheter and arterial catheter, a wake dogs received either N-G-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered end otoxin (50 mu g/kg), then received either N-G-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endo toxin-treated; n = 5). Measurements and Main Results: Both dobutamine and N-G-methyl-L-arginine alone had a small, but significant vasopress or effect on control animals. In contrast, administration of the combi nation of N-G-methyl-L-arginine and dobutamine resulted in a 48.6% inc rease in mean arterial pressure, an effect which was dose-dependent wi th respect to N-G-methyl-L-arginine. In dogs treated with 50 mu g/kg o f endotoxin, hypotension could be only partially reversed by N-G-methy l-L-arginine, mainly due to a decline in cardiac output. Co-infusion o f dobutamine reversed this depression of cardiac output and resulted i n a complete restoration of blood pressure. Conclusions: Later stages of septic shock are characterized by hypotension and decreased myocard ial performance. A major mediator of hypotension is nitric oxide, a va sodilatory agent derived from L-arginine. Administration of the argini ne derivative, N-G-methyl-L-arginine, improved systemic vascular resis tance but not myocardial performance. The addition of an inotropic age nt to N-G-methyl-L-arginine, a nitric oxide synthase inhibitor, result ed in an enhancement of the antihypotensive action of N-G-methyl-L-arg inine through the restoration of cardiac output. The synergistic actio n between dobutamine and N-G-methyl-L-arsnine may be of therapeutic va lue in the treatment of septic shock.