Pharmacological profiles of SKP-450 and its family, a K+ channel opener, in comparison with levcromakalim

This study was carried out to characterise the vasodepressor and vasorelaxant actions of a benzopyran derivative, SKP-450 and its family, (+/-)-racemate SKP-411, (+)-enantiomer SKP-451, and the metabolites of SKP-450 (SKP-818 and SKP-310) in comparison with levcromakalim (LCRK) in the canine coronary, rabbit basilar and vertebral arterial segments. SKP-450, its family (SKP-411 and SKP-451) and the metabolite of SKP-450 (SKP-818) caused concentration-dependent relaxations as well as LCRK in the canine coronary artery and rabbit basilar and vertebral arteries. The relaxant potency of SKP-450 was significantly higher than that of LCRK in the three arteries in terms of EC50 values. SKP-450- and LCRK-induced vasorelaxations were competitively antagonised by glibenclamide with pA2 values of 7.60 (slope 1.22) and 7.99 (slope, 1.00), respectively. SKP-450 (0.1 and 1.0 microM) caused a significant stimulation of the 86Rb efflux from canine coronary arteries in a concentration-dependent manner as well as LCRK (1 and 10 microM), and their effects were antagonised by glibenclamide (10 microM). SKP-450 as well as LCRK produced long-lasting decreases in mean arterial pressure in the spontaneously hypertensive rats (SHR). These results suggest that SKP-450 has a significantly higher potency than LCRK in in vitro vasorelaxation, and it exerts potent and long-lasting vasodepressor effects with its active metabolite (SKP-818).