Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310.
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 mumol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3-100 micrograms/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED20: 9.8, 11.7 and 22.4 micrograms/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3-1,000 micrograms/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 micrograms/kg, respectively). They slightly increased left ventricular positive dP/dtmax 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 (Emax: 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.
Shin
H S
HS
Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea.
Seo
H W
HW
Yoo
S E
SE
Lee
B H
BH
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine; D015221:Potassium Channels / Q000819:agonists*; D011758:Pyrroles / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D011760:Pyrrolidinones; C111830:SKP 310; C111829:SKP 818; D014665:Vasodilator Agents; D019806:Cromakalim; C096762:KR 30450; D009638:Norepinephrine