Vasoplegic endothelial dysfunction in orthotopic liver transplantation.

Abstract

The mechanism of hemodynamic instability during organ transplantation is undoubtedly multifactorial. Although risk factors may be associated with the characteristics of organ receptors, such as reduced levels of vasopressin or diastolic dysfunction of the left ventricle, or related to ischemia time or the surgical technique, it is reasonable to assume that dysregulation of nitric oxide (NO) production leads to increased guanosine 3′5′-cyclic monophosphate (cGMP) synthesis and an organic vasodilation stage probably contributes to vasoplegic syndrome. Classically, the post-reperfusion syndrome is characterized by hypotension and low vascular resistance after blood flow restoration, when cGMP and NO are increased by positive regulation induced by nitric oxide synthase (NOS). The increase in the level of cytokines and endotoxins, resulting in a systemic inflammatory response, is the mediator of the positive NOS regulation. The production of large NO amounts causes vasodilation and oxidative stress. The mechanism of action of methylene blue (MB) is based on the direct inhibition of soluble guanylate cyclase (sGC) by oxidation of the ferrous iron bound to the enzyme. MB also interacts with sGC by binding to the iron heme complex. Consequently, it avoids the increase in cGMP and vascular relaxation mediated by NO, a fact closely linked to the pathophysiology of shock. Another effect of MB is its action as a selective inducible isoform of nitric oxide synthase (iNOS) inhibitor, reducing the overall NO production and preventing the increase in radical peroxynitrite and peroxynitrous acid. In addition to its effect on sGC and iNOS, MB inhibits the production of reactive oxygen species, acting as an alternative electron receptor for xanthine oxidase, competing with molecular oxygen for electron transfer.