Platelet activation guanyl cyclase

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]. 

Further studies revealed that EDRF, like NO, could activate purified cytosolic guanylate cyclase (Ignarro et al., 1986b). Based on this and other observations, we forwarded the hypothesis in 1986 that EDRF is NO or a labile nitroso precursor (Fourth Symposium on Mechanisms of Vasodilatation, Rochester, MN, July, 1986). One year later we (Ignarro et al., 1987a) and others (Palmer et al., 1987) provided chemical evidence to support the view that EDRF is NO. As was first discovered for NO (Mellion etal., 1981), EDRF was shown to inhibit platelet aggregation and adhesion (Radomski et al., 1987). 

Mellion, B. T., Ignarro, L. J., Myers, C. B., Ohlstein, E. H., Ballot, B. A., Hyman, A. L., and Kadowitz, P. J. (1983). Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mol. Pharmacol. 23, 653-664. 

Rodent KC and HC, as well as human HC, express an inducible NO synthase under septic or inflammatory conditions. In vivo in endotoxemia, this expression is transient. Our in vivo data indicate that this induced -NO serves a protective role in the liver and reduces hepatic injury in endotoxemia. This protective action may be mediated by the capacity of NO to neutralize oxygen radicals and prevent platelet adherence and aggregation. Our in vitro studies show that HC-derived -NO can activate soluble guanylate cyclase. Other in vitro effects include the nonspecific suppression of protein synthesis and a small reduction in mitochondrial aconitase activity. The relevance of these in vitro actions to hepatic function in vivo remains to be determined. 

Brune, B., Ullrich, V. (1987). Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol. Pharmacol. 32 497-504. 

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