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).
Hong
K W
KW
Department of Pharmacology, College of Medicine, Pusan National University, Ami-dong 1-Ga, Seo-Gu, Pusan, 602-739, Korea.
Shin
H S
HS
Kim
C D
CD
Shin
Y W
YW
Yoo
S e
Se
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015221:Potassium Channels / Q000819:agonists*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011760:Pyrrolidinones; D014665:Vasodilator Agents; D019806:Cromakalim; C096762:KR 30450