Inhibition of the cGMP/NO in the circulatory shock caused by vasoplegic endothelial dysfunction

• Grant number: 17/03124-3
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2017
• End date: July 31, 2019
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Paulo Roberto Barbosa Evora
• Grantee: Paulo Roberto Barbosa Evora
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Andrea Carla Celotto ; Livia Arcêncio do Amaral ; Tales Rubens de Nadai ; Walusa Assad Gonçalves Ferri

Abstract

Although most shock states are associated with decreased cardiac output, a different situation occurs in cases of shocks due to decreased vascular capacitance where the situation of vasoplegia is associated with elevated cardiac output by configuring a hyperdynamic situation with severe hypotension resistant to High doses of catecholamines. It is important to report that even in this situation myocardial depression may occur with low ejection fractions and biventricular dilatation. Poor prognosis seems to be better correlated with low vascular resistance, leading to the conclusion that vasoplegia is the determining prognostic factor. Thus, paracrine control of vascular capacitance becomes an extremely important factor for clinical and experimental investigations in the search for new pathophysiological and therapeutic knowledge that may contribute to the treatment and prognosis of vasoplegia. It should be noted that vasopressin endothelial dysfunction is associated with all types of shock state.Alongside the fundamental principle of treatment of the cause, the treatment of circulatory shock is still mainly based on volumetric expansion and the use of vasoactive amines, which progressively require increasing doses, associated with high morbidity and mortality. This classical behavior involves the cAMP system without considering the possibility of acting blocking the cGMP system. We have defended the theory that blockade of the cGMP system would be a very reasonable behavior and through a crosstalk mechanism would facilitate the action of the amines with better noradrenaline effects. This possibility has been proven by the use of Methylene Blue in the treatment of circulatory distributive shocks, both from an experimental and clinical point of view.1. To date the whole experience is based on the use of Methylene Blue by the possibility of use in humans. The advantage of cGMP system inhibition would have to be tested using other blockers. It is intended to repeat the experiments performed with AM using the Indigo Carmin and ODQ blockers.2. It is intended to repeat these experiments with different models (for example by the induction of lipopolysaccharide shock, controlled hemorrhage) in different animal species (pigs and rats).3. The hypothesis that blockage of the cGMP/NO system may be detrimental to the pulmonary circulation of neonates, is intended to perform experiments with neonatal pigs.4. To test the isolated experimental evidence of the role of AM as a "protector" of the microcirculation against the increasing concentrations of vasoconstricting amines in the control of refractory arterial hypotension. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

WALUSA ASSAD GONÇALVES-FERRI; AGNES AFRODITE SUMARELLI ALBUQUERQUE; RENATA SAYURI ANSAI PEREIRA DE CASTRO; CRISTINA HELENA FALEIROS FERREIRA; LUIS K. OHAROMARI JR.; DIEGO FERNANDO SILVA LESSA; PAULO ROBERTO BARBOSA EVORA. Methylene Blue to Neonatal Septic Shock treatment in neonate pigs,. Clinics, v. 77, 2023-01-09. (17/03124-3)

GONCALVES-FERRI, WALUSA ASSAD; ALBUQUERQUE, AGNES AFRODITE SUMARELLI; DE CASTRO, RENATA SAYURI ANSAI PEREIRA; FERREIRA, CRISTINA HELENA FALEIROS; OHAROMARI JR, LUIS K.; LESSA, DIEGO FERNANDO SILVA; EVORA, PAULO RENATA BARBOSA. Methylene Blue to Neonatal Septic Shock treatment in neonate pigs. Clinics, v. 77, p. 6-pg., 2022-01-01. (17/03124-3)