Effect of NG-nitro-L-arginine-methyl-ester on cardiopulmonary function and biosynthesis of cyclooxygenase products during porcine endotoxemia.

Abstract

To determine if inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl-ester (L-NAME) potentiates endotoxin-induced cardiopulmonary dysfunction and release of cyclooxygenase products in a porcine model of endotoxemia. Prospective, multiple group, controlled experimental study. Physiologic research laboratory at a veterinary medicine college. Fifty-seven domestic pigs (mean 28.7 +/- 0.8 [SEM] kg). Pentobarbital-anesthetized pigs were intubated and mechanically ventilated to normocapnia with room air. A ther-modilution cardiac output catheter was advanced into the pulmonary artery. Additional catheters were inserted into the jugular and femoral veins and femoral artery. The pigs received the following infusions: saline (control, n = 5); L-NAME (0.1, 0.5, 2.2, or 5.5 mg/ kg/hr, from -0.5 to 2 hrs, n = 16); Escherichia coli endotoxin (5 micrograms/ kg from 0 to 1 hr followed by 2 micrograms/kg from 1 to 2 hrs, i.v., n = 14); L-NAME plus endotoxin (n = 9); indomethacin plus endotoxin (n = 6); or L-NAME indomethacin plus endotoxin (n = 7). L-NAME significantly (p < .05) worsened endotoxin-induced hypoxemia and enhanced the increases in pulmonary vascular resistance index and systemic vascular resistance index at 30 to 60 mins. Endotoxin increased (p < .05) plasma concentrations of thromboxane B2 by seven- to eight-fold at 30 to 120 mins and 6-keto-prostaglandin F1 alpha by 16- to 24-fold at 60 to 120 mins. L-NAME enhanced (additive effect) endotoxin-induced increases in plasma concentrations of thromboxane B2 (60 mins) and significantly (p < .05) potentiated the increases in 6-keto-prostaglandin F1 alpha (120 mins). At 120 mins of endotoxemia, indomethacin (cyclooxygenase inhibitor) plus L-NAME markedly increased (p < .05, synergistic effect) systemic vascular resistance index compared with endotoxemic pigs pretreated with either L-NAME or indomethacin. During endotoxemia, inhibition of nitric oxide synthase with L-NAME may be deleterious to cardiopulmonary function, as evidence by potentiation of endotoxin-induced systemic and pulmonary vasoconstriction, impairment of gas exchange, and enhanced biosynthesis of cyclooxygenase products. Moreover, during endotoxemia, the concomitant inhibition of two important vasodilators (i.e., nitric oxide and prostacyclin) is associated with a potentiated (p < .05) increase in systemic vascular resistance index.