The Guanylyl Cyclase Inhibition by MB as Vasoplegic Circulatory Shock Therapeutical Target

Abstract

There were strong evidences that NO has capital importance in the progressive vasodilatation that associates to the varied circulatory shock forms. The decreased systemic vascular resistance observed in irreversible hemorrhagic (hypovolemic) and septic shock may be due to the excess production of nitric oxide. Other forms of shock associated to anaphylaxis (anaphylactic shock, SIRS) and ischemia reperfusion injury (cardiogenic shock, organ transplants), may involve nitric oxide overproduction. In these situations, the nitric oxide-induced loss of vascular sensitivity to catecholamines and myocardial depression contributes to lethal hypotension. As NO vasodilatation is cyclic GMP-mediated, there were two therapeutical options: a) The unspecific NO synthesis inhibition by L-arginine analogs, iNOS-specific inhibition by corticoids and/or aminoguanidine and; b) Guanylyl cyclase inhibition by MB. As the NO synthesis inhibition is associated to tissue necrosis and adverse hemodynamic effects and its clinical use was associated with high mortality, the second option using MB is safer and more rational. The elaboration of this text was motivated to suggest the guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutical target.

Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties

“…Observing the other 55 studies we can find: 1) one study (1.67%) based on evidences through metanalysis of literature [13]; 2) seven review articles (11.67%) [4,14,23]. The other bibliographical citations in number of 44 (73.33%) are distributed as case reports (great majority) [24][25][26][27][28][29][30][31][32][33][34][35][36], letters [37][38][39][40][41][42][43][44], technical aspects of the MB use [45][46][47][48][49][50] and other studies involving risk [51,52], the VS incidence in the "off pump" CABG and the possibility of MB use in anaphylaxis and anaphylactic shock [53], also a proposal of the author of this text ( Figure 4) [54][55][56][57][58].…”

“…These pathophysiology data, presented in a generic sense, may be reviewed by at least three references cited in the text provided [13,14,18]. From these concepts a certainty emanates, that is: the VS is a consequence of systemic inflammatory reaction, being, therefore, an endothelial vasoplegic dysfunction [37].…”

Anaphylaxis with Latrodectus Antivenin Resulting in Cardiac Arrest

“…Methylene blue has been used over the last several years as a treatment for intractable hypotension in anaphylaxis, sepsis, and vasoplegia from cardiopulmonary bypass during cardiac surgery [32][33][34][35]. Multiple case reports document the reversal of anaphylactic symptoms, including druginduced cardiac arrest and angioedema, after patients receive methylene blue [36][37][38].…”

“…Multiple case reports document the reversal of anaphylactic symptoms, including druginduced cardiac arrest and angioedema, after patients receive methylene blue [36][37][38]. Methylene blue inhibits soluble guanylyl cyclase, preventing vasodilation and decreasing associated vascular permeability by limiting the effect of nitric oxide [32,36]. Evora and several others report rapid improvement of several patients who failed standard therapy with epinephrine, antihistamines, and steroids after developing hypotension with or without associated angioedema [36][37][38].…”

Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

“…The same group also found methylene blue to be effective in the treatment of a small number of patients suffering from anaphylactic shock [271]. The usage of methylene blue in the treatment of septic shock has been reviewed recently [272], concluding that in spite of well-proven effects on the hemodynamics an improvement of oxygen delivery and of mortality has not been studied sufficiently.…”