Effects of levcromakalim and glibenclamide on paced guinea-pig atrial strips exposed to hypoxia.
Isolated strips of guinea-pig atrial myocardium were mounted in isometric myographs and electrically paced for measurements of myocardial contractile function. Levcromakalim, a K+ channel opener, completely inhibited the contractile force in a concentration-dependent way (EC50 = 15 microM). Glibenclamide (3 microM), a blocker of ATP-regulated K+ channels (KATP), caused a 5-fold rightward shift of the concentration-effect curve. Exposure of the atrial strips to hypoxia caused a time-dependent loss of contractility from 100% to a minimum level of 60% within 12 min. Levcromakalim (1 microM, 3 microM and 10 microM) concentration-dependently enhanced the hypoxia-induced inhibition of contractile function whereas levcromakalim (0.01 microM and 0.1 microM) had no significant effect. In the presence of levcromakalim (10 microM) hypoxia reduced the contractile force to 25%. Glibenclamide (3 microM) totally antagonized the enhancing effect of levcromakalim. When hypoxia was induced in glucose-free Krebs solution with 2-deoxyglucose, the myocardial contractility was completely suppressed within 12 min. Glibenclamide by itself (3 microM) failed to influence the myocardial response to hypoxia both in normal Krebs solution and under conditions of impaired glycolysis. The results indicate that levcromakalim by activation of myocardial ATP-regulated K+ channels accelerates and enhances the hypoxia-induced inhibition of myocardial contractile function. This effect may possibly contribute to the mechanism by which K+ channel openers exert cardioprotection. The results further suggest that mechanisms different from activation of KATP take a major part in the depressant mechanical response to hypoxia and glycolytic blockade in the guinea-pig atrial myocardium.
Mellemkjaer
S
S
Department of Pharmacology, University of Aarhus, Denmark.
Nielsen-Kudsk
J E
JE
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D019806:Cromakalim; D003847:Deoxyglucose / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*
D001578:Benzopyrans; D010276:Parasympatholytics; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D003847:Deoxyglucose; D005905:Glyburide