Endothelin-1 and blood pressure after inhibition of nitric oxide synthesisin human septic shock

Background-The systemic hypotension during human sepsis has been ascribed t o increased production of nitric oxide (NO), Therefore, inhibitors of NO sy nthesis have been used in the treatment of hypotension in patients with sep tic shock. In addition, NO production may inhibit the synthesis and vasocon strictor effects of endothelin-1 (ET-1). In this study, we tested whether E T-1 contributed to the vasopressor action of the NO synthase inhibitor N-G- nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock . Methods and Results-Compared with healthy volunteers, patients with septic shock had increased plasma levels of nitrite/nitrate (37 +/- 5 [SEM] versus 12 +/- 5 mmol/L, P<0.01), the stable end products of NO metabolism, and ET -1 (45 +/- 7 versus 3 +/- 2 pg/mL, P<0.001). Plasma ET-1 concentration was not related to plasma nitrite/nitrate concentration or blood pressure. Cont inuous infusion of L-NAME (1 mg . kg(-1) . h(-1) IV) for 12 hours increased mean arterial pressure by 43 +/- 5% and systemic vascular resistance by 64 +/- 10% (both P<0.01). The increase in blood pressure and systemic vascula r resistance correlated positively with the level of ET-1 (both P<0.005) bu t not with plasma nitrite/nitrate level. L-NAME infusion did not result in significant changes in the plasma concentrations of ET-1 or nitrite/nitrate . Conclusions-NO and ET-1 may both play a role in the cardiovascular derangem ents of human sepsis. Although L-NAME does not increase ET-1 concentration in patients with septic shock, the vasopressor response induced by L-NAME d epends on the plasma level of ET-1, These findings may indicate that inhibi tors of NO synthesis unmask a tonic presser response of ET-1 in human septi c shock.