NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs

Abstract

Objective: To evaluate the hemodynamic effects of the nitric oxide inhibitor, NG-methyl-L-arginine, and dobutamine during experimental endotoxemia. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Adult, male mongrel dogs. Interventions: After catheterization with a flow-directed, thermal-dilution pulmonary artery flotation catheter and arterial catheter, awake dogs received either NG-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered endotoxin (50 μg/kg), then received either NG-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endotoxin-treated; n = 5). Measurements and Main Results: Both dobutamine and NG-methyl-L-arginine alone had a small, but significant vasopressor effect on control animals. In contrast, administration of the combination of NG-methyl-L-arginine and dobutamine resulted in a 48.6% increase in mean arterial pressure, an effect which was dose-dependent with respect to NG-methyl-L-arginine. In dogs treated with 50 μg/kg of endotoxin, hypotension could be only partially reversed by NG-methyl-L-arginine, mainly due to a decline in cardiac output. Co-infusion of dobutamine reversed this depression of cardiac output and resulted in a complete restoration of blood pressure. Conclusions: Later stages of septic shock are characterized by hypotension and decreased myocardial performance. A major mediator of hypotension is nitric oxide, a vasodilatory agent derived from L-arginine. Administration of the arginine derivative, NG-methyl-L-arginine, improved systemic vascular resistance but not myocardial performance. The addition of an inotropic agent to NG-methyl-L-arginine, a nitric oxide synthase inhibitor, resulted in an enhancement of the antihypotensive action of NG-methyl-L-arginine through the restoration of cardiac output. The synergistic action between dobutamine and NG-methyl-L-arginine may be of therapeutic value in the treatment of septic shock. (Crit Care Med 1994; 22:1835–1840)