Hypotensive effect of 3-(3-[1,2,4]triazolo)-oxatriazolium-5-olate is caused by NO-independent activation of soluble guanilate cyclaseстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 27 мая 2015 г.
Аннотация:Soluble guanylate cyclase (sGC) is a crucial enzyme at NO/cGMP-mediated vasodilation. There are NO-independent mechanisms of sGC activation besides well-known enzyme activation by endogenous or exogenous NO. Since 1966 oxatriazolium-5-olate derivates are known as hypotensive agents at narcotized animals (Kier LB et al., 1966). But the mechanism of their activity is not clarified. The goal of this research is to examine the ability of 3-(3-[1,2,4]triazolo)-oxatriazolium-5-olate (AS-6) to generate NO, to activate sGC, and to alter systemic arterial pressure at awake rats. Methods. The ability of AS-6 to generate NO was estimated by its reaction with oxyhemoglobin in the presence and absence of glutathione. Also NO (nitrite) formation in the presence of AS-6 was measured by the Griess reaction. Activity of sGC was measured by using purified enzyme from porcine lung in the presence of 10-200 microM AS-6 with alpha-[32P]GTP as a substrate. To examine hypotensive activity of AS-6 male Wistar rats (200-300 g weight) were catheterized and mean arterial pressure was measured. AS-6 was administrated at doses 0.012-120 mg/kg to rats of experimental group in two days. Control group were administrated with corresponding DMSO solutions. Results. We demonstrated that AS-6 doesn’t generate detectable levels of NO both in the presence and absence of glutathione. AS-6 activated purified sGC in dose-dependent manner with 22-fold maximal activation. This activation could be potentiated by allosteric sGC activator YC-1 and completely inhibited by heme-dependent sGC blocker ODQ. In vivo AS-6 caused MAP decrease, 5.4 and 8.4 mm Hg, (p<0.05) at doses 12 mg/kg and 120 mg/kg, respectively. MAP was significantly decreased from 15th min and was stably reduced for 15 min. Conclusion. Intravenous administration of AS-6 leads to prolonged arterial pressure decrease in awake rats. It seems to be that AS-6 activates sGC in heme-dependent NO-independent manner.