Increased production of nitric oxide by neutrophils and monocytes from cirrhotic patients with ascites and hyperdynamic circulation

Abstract

An increased release of nitric oxide (NO), a powerful vasodilating agent, has been proposed to play a role in the pathogenesis of vasodilation and hyperdynamic circulation associated with advanced cirrhosis. We evaluated NO synthase (NOS) activity in peripheral leukocytes of 12 cirrhotic patients and 9 healthy subjects together with plasma endotoxin levels and systemic hemodynamic (by a noninvasive echocardiographic method). NOS activity was evaluated by (1) measuring the capacity of isolated polymorphonuclear cells (PMNs) and monocytes to convert [ 3[H]arginine to [ 3[H]citrulline; (2) measuring the ability of neutrophils and monocytes to inhibit thrombin-induced platelet aggregation and to increase guanosine 3′-5′-cyclic monophosphate content in coincubated platelets, an expression of NO release from these cells. Both neutrophils and monocytes from cirrhotic patients produced significantly higher amounts of [ 3h]citrulline than cells obtained from healthy subjects ( P < .001 and P < .02 for neutrophils and monocytes, respectively) and were more effective than control cells in inhibiting platelet aggregation ( P < .05 and P < .001, respectively for 2 ×10 6 cells) and in increasing guanosine 3′-5′-cyclic monophosphate content in coincubated platelets ( P < .05 and P < .001, respectively). The anti-aggregating activity expressed by leukocytes has a pharmacological profile similar to that described for NO, because it increased after addition of superoxide dismutase, a superoxide anion scavenger, and markedly decreased after inhibition of nitric oxide synthesis with N G-monomethyl- l-arginine (L-NMMA) and N G -nitro- l-arginine-methyl ester (LNAME). Cirrhotic patients had significantly higher plasma endotoxin levels ( P < .001) and cardiac index ( P < .01) when compared with controls. These data support the contention that the NO synthetic pathway is activated in cirrhotic patients with ascites, hyperdynamic circulation, and endotoxemia.