Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310.

Abstract

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.

• Authors: H S Shin, H W Seo, S E Yoo, B H Lee
• Journal: Pharmacology (Pharmacology) Vol. 56 Issue 3 Pg. 111-24 (Mar 1998) ISSN: 0031-7012 [Print] Switzerland
• PMID: 9532610 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antihypertensive Agents
• Benzopyrans
• Potassium Channels
• Pyrroles
• Pyrrolidinones
• SKP 310
• SKP 818
• Vasodilator Agents
• Cromakalim
• KR 30450
• Norepinephrine

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Aorta, Thoracic (drug effects)
• Benzopyrans (administration & dosage, pharmacology)
• Coronary Circulation (drug effects)
• Cromakalim (pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Hemodynamics (drug effects)
• In Vitro Techniques
• Male
• Muscle Contraction
• Muscle, Smooth, Vascular (drug effects)
• Norepinephrine
• Potassium Channels (agonists)
• Pyrroles (pharmacology)
• Pyrrolidinones (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)