Cardiovascular Therapeutics Targets on the NO–sGC–cGMP Signaling Pathway: A Critical Overview

Paulo      Roberto B. Evora; Patricia      M. Evora; Andrea      C. Celotto; Alfredo      J. Rodrigues; Edwaldo      E. Joviliano

Abstract

In a brief overview, in NO–sGC–cGMP signaling in a blood vessel, l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Heme-dependent sGC stimulators and hem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. Studies of the 90´s definitively established the role of endothelium in all cardiovascular diseases, which were associated with endothelial dysfunction by impaired release of endothelium-derived relaxing factors with consequent risk of spasm and thrombosis. The rationale of this review is based on the fact that the discovery of NO changed the concepts of cardiovascular disease mechanisms. However, considering the jargon "from the bench to clinical practice" we concluded that a potential therapeutic revolution did not follow the pathophysiological revolution. The review is focused on general aspects without regard for advanced research aspects, and designed in two main groups: the NO/cGMP positive stimulators and blockers as “future and encouraging” new therapeutic drugs. The potential vasodilators include 1) NOS uncoupling; 2) NOS enhancers (AVE compounds); 3) NO donors (nitrovasodilators); 4) NOindependent activators (BAY compounds), and; 5) PDE5 inhibitors. The potential vasoconstrictors include 1) NOSblockers (L-NAME, L-NMMA); 2) sGC-blockers (methylene blue), and; 3) PDEs. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental and clinical experience working on vasoplegic endothelium dysfunction.

Keywords: Nitric oxide, nitric oxide synthase, nitric oxide enhancers, nitric oxide uncoupling, nitric oxide blockers, soluble guanylate cyclase, NO–sGC–cGMP signaling, endothelial dysfunction, cardiovascular disease, stimulators