Biased agonists for the Gq protein pathway in the a1-adrenoceptor subtypes in Septic Vasoplegia treatment

Abstract

Sepsis is a complex syndrome triggered by a systemic inflammatory response to an infection. It is characterized by hemodynamic, cellular and metabolic events such as: fever or hypothermia, altered heart rate, leukocytosis or leukopenia, lactic acidosis and loss of vascular tonus (vasoplegia) leading to hypotension and hypoperfusion of vital organs (Dellinger et al., 2013; Duan et al., 2015). In some cases, the sepsis-induced vasoplegia is refractory even after adequate fluid replacement, resulting in organ failure and septic shock (Gamcrlidze et al., 2015; Geloen et al., 2015). Vasopressor drugs are used for the treatment of this condition and the catecholamine noradrenaline is the first line drug (Geloen et al., 2015). Noradrenaline induces vasopressor responses by activating a1-adrenoceptors on the vascular smooth muscle (Bangash et al., 2012). a1-Adrenoceptors are divided into three subtypes (a1A, a1B and a1D) and all of them activate the Gq/11 protein to stimulate intracellular Ca2+ mobilization and activation of protein kinase C, leading to the contraction of vascular smooth muscle (Amberg & Navedo, 2013). Clinical evidence has shown vascular hyporesponsiveness in septic shock despite elevated levels of endogenous and exogenous catecholamines, compromising the efficacy of the treatment and increasing the mortality rates in septic shock patients (Levy et al., 2010; Geloen et al., 2015). The exact mechanism behind the catecholaminergic hyporesponsiveness is still not fully understood, but it is described that a1-adrenoceptor desensitization could be responsible for the lack of vasopressor responses to catecholamines in septic shock (Ghosh & Liu, 1983; Hwang et al., 1994; Geloen et al., 2015). a1-Adrenoceptor desensitization can be mediated by a G-protein independent process with involvement of a distinct signaling pathway elicited by b-arrestins recruitment, which are able to induce receptor internalization (Stanasila et al., 2008; Akinaga et al., 2013; Pupo et al., 2016). In this context, recent studies have shown that some ligands for G-protein coupled receptors are able to preferentially activate (biased agonism) a particular signalling pathway (p. ex. G-protein-related) when compared to other (p.ex. b-arrestin-related) and this pharmacological phenomenon may lead to important clinical implications (Rajagopal et al., 2010; Kenakin & Christopoulos, 2013). Therefore, this study aims to evaluate in vitro and in vivo the biased agonism of several ligands at a1-adrenoceptor subtypes, identifying compounds with bias towards the G-protein pathway (Ca2+ mobilization, vasoconstriction) compared to b-arrestin pathway (desensitization/internalization of receptors). The results of this study will indicate more efficacious compounds for the treatment of sepsis-induced vasoplegia, improving the outcome and survival of patients with septic shock.