Soluble guanylate cyclase activation

Nitric oxide (NO) is synthesized by vascular endothelium in response to vasodilators. It diffuses into the surrounding vascular smooth muscle, where it directly binds the heme group of soluble guanylate cyclase, activating the enzyme. 

Pietta PG, Mauri PL, Gardana C, Benazzi L. Assay of soluble guanylate cyclase activity by isocratic high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1997 690 343-347. 

Ignarro, L. J., Ballot, B., and Wood, K. S. (1984a). Regulation of soluble guanylate cyclase activity by porphyrins and metalloporphyrins.). Biol. Chem. 259, 6201-6207. 

Kojda, G., Laursen, J.B., Ramasamy, S., Kent, J.D., Kurz, S., Burchfield, J., Shesely, E.G., Harrison, D.G. Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial cell nitric oxide synthase contributions of NOS isoforms to blood pressure and heart rate control, Cardiovasc. Res. 1999, 42, 206-213. 

Buechler, W. A., Nakane, M., and Murad, F. (1991). Expression of soluble guanylate cyclase activity requires both enzyme subunits. Biochem. Biophys. Res. Commun. 174, 351-357. 

Lewicki, J. A., Brandwein, H. J., Mittal, C. K., Arnold, W. P., and Murad, F. (1982). Properties of purified soluble guanylate cyclase activated by nitric oxide and sodium nitroprusside. J. Cyclic Nucleotide Res. 8, 17-25. 

Isatin, an endogenous indole, can be transported to human platelets, where it inhibited NO-stimulated soluble guanylate cyclase activity (Medvedev et al. 2002). The effect was most pronounced at 10" M isatin and is the most potent effect of isatin yet observed. The dose response curve was bellshaped with higher doses becoming less effective. The maximal inhibition observed was 40 %. Isatin had no effect of protoporphyrin IX-stimulated guanylate cyclase. 

Severina, I.S., Belushkina, N.N., and Grigoryev, N.B. (1994). Inhibition of Adp-induced human platelet aggregation by a new class of soluble guanylate cyclase activators capable of nitric oxide generation. Biochem. Mol. Biol. Int. 33, 957-967. 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

In vitro activation of soluble guanyl cyclase and nitric oxide release a comparison of NO donors and NO mimetics Biochemistry 40 (2001),... 

Dimethyl-l,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (41) is also an old product [7,11, 31] that has recently been found to react with GSH to give S-nitrosogluta-thione, NO and HNO [32]. It stimulates partially purified rat lung soluble guanylate cyclase, but not the heme-deficient enzyme. The activation is inhibited by ODQ. The product also displays significant vasodilator activity on rat thoracic aorta rings at nanomolar concentrations. Finally, [l,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide derivatives (42, R,Ri=CH3,H) release NO, detected as nitrite, in the presence of thiols. A mechanism for this release has been proposed [33]. 

Mesoionic oxatriazolium-5-amenates 83 exhibit the whole range of biological properties typical of NO-releasing compounds that stimulate soluble guanylate cyclase namely antihypertensive activity in animals following the relaxation of the vascular... 

In its raw form, exogenous NO donation as pure NO gas must be considered as a possible therapeutic route. Unlike all previous subdivisions, administration of this kind is obviously independent of any chemical or enzymatic process prior to the activation of soluble guanylate cyclase. This route lacks sophistication, and can... 

DETA/NO is a stable NO-donor with the longest NO generation half-life of approximately 20 h. Thrombelastography performed on rabbit blood showed that DETA NONOate-derived NO significantly decreased coagulation activity and platelet activation [48]. Monitoring by intravital microscopy showed that DETA/NO attenuated the platelets/endothelial cells adhesion response to endotoxins (e.g. lipopolysaccharides) in murine intestinal venules [49]. The main mechanism of the antiadhesive action of DETA/NO on platelets was activation of soluble guanylate cyclase [49]. 

---