In vitro pharmacological characteristics of SKP-450, a novel K+ channel opener, in non-vascular smooth muscles in comparison with levcromakalim

ABSTRACT

In the present study, we characterized the non-vascular smooth muscle relaxant effects of a novel benzoyran derivative, SKP-450 (2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro- 2H-1-benzopyran) and its metabolite, SKP-310, in comparison with levcromakalim (LCRK). In the rat stomach fundus, the spontaneous motility stimulated by 10-6.5 M bethanechol was completely eliminated not only by 10(-7) M SKP-450 but also by 10(-6) M LCRK, which were blocked by 10(-6) M glibenclamide. The inhibitory effect of SKP-450 (pD2, 3.94 +/- 0.66) was much less than LCRK (pD2, 5.73 +/- 0.38, P < 0.05). In the bethanechol (10(-6.5) M)-stimulated urinary bladder, the tonus was decreased in association with elimination of spontaneous motility by 10(-7) M SKP-450 and 10-6 M LCRK (pD2, 6.77 +/- 0.06) (P < 0.05), which were inhibitable by 10-6 M glibenclamide. The inhibitory effect of SKP-450 (pD2, 7.66 +/- 0.05) was significantly more potent than that of LCRK (pD2, 6.77 +/- 0.06, P < 0.05). In the rat uterus stimulated by PGF2alpha (10(-7) M), both increased tonus and spontaneous motility were eliminated by 10(-6) M LCRK with slight depression of the tonus, but not by SKP-450 (10(-5) M). The stimulated trachea of guinea-pig by 10-6.5 M bethanechol was moderately suppressed by SKP-450 (10(-6)~10(-5) M) but little by SKP-310. In association with the relaxant effects, SKP-450 (10(-6) M) and LCRK (10(-5) M) caused a significant stimulation of the 86Rb efflux from rat urinary bladder and stomach fundus, which were antagonized by 10(-5) M glibenclamide, whereas the K+ channel openers could not exert a stimulation of the 86Rb efflux from rat uterus. In conclusion, it is suggested that SKP-450 exerts potent relaxant effects on the urinary bladder detrusor muscle and duodenum, whereas it shows much less effect on stomach fundus and uterus as contrasted to LCRK.