After Thirty Years, We Still Cannot Understand Why Methylene Blue is not a Reference to Treat Vasoplegic Syndrome in Cardiac Surgery

Fig. 1. The classical endothelial nitric oxide (NO) release pathway requires 1) signal transduction from a cell receptor-mediated by G proteins (Gp); 2) phospholipase C (PLC) activation and production of inositol triphosphate (IP3) from phosphatidylinositol 4,5-biphosphate (PIP2) and cytosolic Ca2+ release; 3) the constitutive endothelial NO synthase (eNOS) is activated by complex Ca2+/calmodulin and produces NO from its substrate L-arginine; 4) NO stimulates guanylate cyclase in adjacent smooth muscle cells, which causes an increase in cyclic guanosine monophosphate (cGMP) that is the final stimulus that causes vasorelaxation; and 5) methylene blue inhibits the activity of guanylate cyclase, decreasing the cGMP production and less vascular smooth muscle relaxation (adapted from Evora et al., 2009[1]). GTP=guanosine triphosphate; R=receptor

Fig. 2. The three mechanisms of vasodilatation. cAMP=3’,5’-cyclic adenosine monophosphate; cGMP=cyclic guanosine monophosphate; EDRFs=endothelium-derived relaxing factors; NO=nitric oxide; PGI2=prostacyclin

Fig. 3. Vasodilator and antiplatelet actions of nitric oxide (NO). 5-HT=5- hydroxytryptamine; ADP=adenosine diphosphate; EDRF=endothelium-derived relaxing factor; TXA2=thromboxane A2

Fig. 4. Schematic points of the “crosstalk” between cyclic guanosine monophosphate (cGMP) (nitric oxide [NO]) and 3’,5’-cyclic adenosine monophosphate (cAMP) (prostacyclin). ATP=adenosine triphosphate; Gp=Gp proteins; GS=Gs proteins; GTP=guanosine triphosphate; iNOS=inducible nitric oxide synthase; IP3=inositol triphosphate; MB=methylene blue; PGH2=prostaglandin H2; PGI2=prostacyclin; PIP2=phosphatidylinositol 4,5-biphosphate; PLC=phospholipase C; R=receptor; sGC=soluble guanylyl cyclase

Fig. 5. Graph presentation of the increased number of papers as time goes by (Medical Literature Analysis and Retrieval System Online - MEDLINE).

Fig. 6. Photograph of rat mesenteric microcirculation showing the excellent structure after Escherichia coli lipopolysaccharide injection. The # shows the venula; the arrows show almost normal leukocyte adhesion. LPS=; MB=methylene blue