title: Antihypertensive effects of the novel potassium channel activator SKP-450 and its major metabolites in rats.
abstract: 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.
authors.affiliation: Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon.
authors.forename: H S
authors.initials: HS
authors.lastname: Shin
authors.forename: H W
authors.initials: HW
authors.lastname: Seo
authors.forename: J H
authors.initials: JH
authors.lastname: Oh
authors.forename: B H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D019806:Cromakalim / Q000494:pharmacology; D003900:Desoxycorticosterone; D006339:Heart Rate / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D015221:Potassium Channels / Q000819:agonists*; D011758:Pyrroles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D011760:Pyrrolidinones; C111830:SKP 310; C111829:SKP 818; D014665:Vasodilator Agents; D019806:Cromakalim; D003900:Desoxycorticosterone; C096762:KR 30450