SKP-818

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).

The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450>SKP-818>lemakalim>SKP-310 (EC₅₀: 0.12, 0.55, 0.71 and 5.89 µmol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3–100 µg/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED₂₀: 9.8, 11.7 and 22.4 µg/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3–1,000 µg/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED₂₀: 2.6, 4.2 and 588.8 µg/kg, respectively). They slightly increased left ventricular positive dP/dt_max with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (E_max: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.