ANTIHYPERTENSIVE EFFECTS OF THE NOVEL POTASSIUM CHANNEL ACTIVATOR SKP-450 AND ITS MAJOR METABOLITES IN RATS

Antihypertensive effects of SKP-450 (KR-30450, CAS 172489-10-0, -(2'-o xopyrrolidin-1-yl)-6-nitro-2H-1-benzopyran), a newly synthesized potas sium channel activator, and its major metabolites SKP-818 4-(2'-oxopyr rolidin-1-yl)-6-nitro-2H-1-benzopyran) and SKP-310 4-(2'-oxopyrrolidin -1-yl)-6-nitro-2H-1-benzopyran) were evaluated in freely moving sponta neously hypertensive (SHR), renally hypertenisve (RHR), DOCA/salt-indu ced 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 mu g/kg, p.o.) and SKP-818 ( 3-100 mu g/kg, i.v.) dose-dependently decreased mean arterial pressure (MAP) (potency order: SKP-450, RHR > SHR = DHR > NR; SKP-818, DHR = S HR = 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 equi potent in RHR and DHR. Repeatedly administration of SKP-450 to SHR ove r 21 days (10 and 30 mu g/kg, p.o., once a day), had no significant ef fect on the degree and pattern of its antihypertensive effects and on the reactivity of isolated aorta to various vasoconstrictors and vasod ilators. These results suggest that SKP-450 is a potent peripheral vas odilator acting without the development of tolerance and the alteratio n in vascular reactivity. SKP-818 and SKP-310 may play a role as an ac tive metabolite and inactive intermediary, respectively.