YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits the spontaneous contractions of isolated pregnant rat myometrium
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The aim of this study was to investigate the effect of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole) on spontaneous contractions and levels of cyclic GMP (cGMP) of myometrial strips isolated from pregnant rats. It is a nitric oxide-independent soluble guanylate cyclase activator. Myometrial strips were obtained from eight pregnant Wistar albino rats and were mounted in organ baths for the recording of isometric tensions. We evaluated the effect of increasing concentrations of YC-1 on spontaneous myometrial contractions and on contractions of myometrial smooth muscle pretreated with methylene blue (10(-5) M), tetraethylammonium chloride (TEA) (3 x 10(-4) M), and glibenclamide (10(-6) M). YC-1 (10(-9)-3 x 10(-5) M) concentration-dependently decreased the amplitude and frequency of spontaneous contractions of myometrial strips. The inhibition of the amplitude and frequency of spontaneous contractions by YC-1 were antagonized with methylene blue (10(-5) M) and TEA (3 x 10(-4) M), but they were not changed by glibenclamide (10(-6) M); however, the antagonistic effect of methylene blue was significantly more than that of TEA (P<0.05). We also evaluated the effect of YC-1 on the levels of cGMP in myometrial strips obtained from pregnant rat uterine horns. YC-1-stimulated myometrial strips showed an excessive elevation in myometrial cGMP that declined slowly during the subsequent washout period. These results show that YC-1 decreases spontaneous contractile activity of myometrial strips isolated from pregnant rat and causes elevation of myometrial cGMP levels in vivo. This effect of YC-1 is significantly reduced by the methylene blue and TEA, suggesting the activation of soluble guanylate cyclase and Ca2+-sensitive K+ channels as the mechanisms of action.