Presence of a nitric oxide synthase inhibitor in the graft efflux during reperfusion in human liver transplantation

Abstract

Involvement of the nitric oxide (NO) system in complications following human orthotopic liver transplants (OLT) has been reported, but the contribution of the graft to the modulation of the NO system during reperfusion in normal OLT has not been characterized. We have studied the contribution of the graft efflux to the modulation of the NO system in 20 consecutive OLT. We evaluated its effects on isolated vascular reactivity of the rabbit and on rat cultured macrophages stimulated with lipopolysaccharide (LPS). In none of the donor liver biopsies was expression of inducible NO synthase (iNOS) activity by Northern or Western blot analysis found. Graft efflux after the onset of liver reperfusion, but not pre-transplant patient plasma, reversibly inhibited the acetylcholine-induced relaxation of norepinephrine-contracted rabbit aortic rings. Moreover, graft efflux reversibly inhibited NO production in rat macrophages treated with LPS, as evidenced by both a decrease in nitrite plus nitrate formation and a decrease in the production of [14C]citrulline from [14C]arginine. Addition of a 10% dilution of graft efflux to cultured rat macrophages incubated with LPS increased iNOS mRNA levels, suggesting direct inhibition of the enzyme but not of its expression. These results cannot be ascribed to the depletion of arginine the iNOS substrate since they can be reproduced even in the presence of an excess (10 mM) of exogenously added arginine. No correlation was found between the iNOS inhibitory activity in each sample and the corresponding clinical parameters related to either the graft function after the OLT or the existence of post-reperfusion syndrome. Our results indicate the existence of a soluble factor in the graft efflux from human OLT that reversibly and unspecifically inhibits NOS activity. Its involvement in the physiology and/or pathology of human liver diseases deserves further study.

Protective Role of Hepatocyte Cyclooxygenase‐2 Expression Against Liver Ischemia–Reperfusion Injury in Mice

“…From a translational point of view, we evaluated the relationship between PGE 2 levels in plasma and the clinical data of patients undergoing LT . Interestingly, clinical data obtained in the context of LT showed a significant association between arterial PGE 2 levels and early graft function, evaluated by a well‐known scale that has been employed in previous publications .…”

Nafamostat Mesilate Attenuates Postreperfusion Syndrome during Liver Transplantation

“…In the early observation of PRS, Aggarwal and colleagues suspected that hypotension after reperfusion of the liver graft is caused by the release of 'yet to be defined vasodilating substances' from the liver graft (15). Subsequent studies demonstrated that undefined substances released during ischemia reperfusion of the liver graft contribute toward cardiovascular instability through activation of the complement system and the kallikreinkinin system, negative effect on cardiac performance, or inhibition of nitric oxide synthase (8,(16)(17)(18). Among the above, the potent vasodilating action of bradykinin, a product of the kallikrein-kinin system, has been considered the most likely cause of PRS.…”

Role of cyclooxygenase-2 in ischemia-reperfusion injury in the liver

“…Finally, the contribution of COX-2 to the prevention of tissue damage after I/R was analysed in the context of clinical translation. In this study, the relationship between plasma PGE2 levels and clinical data of patients undergoing LT has been evaluated [273]. This analysis shows that the presence of PGE2 in the plasma of recipients correlates with a better prognosis, while lower PGE2 levels are associated with early graft disfunction, assessed with a previously described scale [274].…”