Antihypertensive effects of the novel potassium channel activator SKP-450 and its major metabolites in rats.

摘要

Antihypertensive effects of SKP-450 (KR-30450, CAS 172489-10-0, (-)-(2R)-2"-(1",3"-dioxolan-2-yl)-2-2methyl-4-(2'-oxopyrr olidin-1-yl)-6- nitro-2H-1-benzopyran), a newly synthesized potassium channel activator, and its major metabolites SKP-818 ((-)-(2R)-2"-hydroxymethyl-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-ni tro- 2H-1-benzopyran) and SKP-310 ((-)-(2R)-2"-carboxy-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro-2H -1- benzopyran) were evaluated in freely moving spontaneously hypertensive (SHR), renally hypertenisve (RHR), DOCA/salt-induced hypertensive (DHR) and normotensive rats (NR). The effects of long-term treatment with SKP-450 on blood pressure and arterial reactivity were also studied in SHR. SKP-450 (3-300 micrograms/kg, p.o.) and SKP-818 (3-100 micrograms/kg, i.v.) dose-dependently decreased mean arterial pressure (MAP) (potency order: SKP-450, RHR > SHR = DHR > NR; SKP-818, DHR = SHR = RHR > NR); however, SKP-310 did not influence MAP. Compared with lemakalim, SKP-450 was 2 to 5 fold more potent in SHR and NR, and equipotent in RHR and DHR. Repeatedly administration of SKP-450 to SHR over 21 days (10 and 30 micrograms/kg, p.o., once a day), had no significant effect on the degree and pattern of its antihypertensive effects and on the reactivity of isolated aorta to various vasoconstrictors and vasodilators. These results suggest that SKP-450 is a potent peripheral vasodilator acting without the development of tolerance and the alteration in vascular reactivity. SKP-818 and SKP-310 may play a role as an active metabolite and inactive intermediary, respectively.