EFFECTS OF LEVCROMAKALIM AND GLIBENCLAMIDE ON PACED GUINEA-PIG ATRIALSTRIPS EXPOSED TO HYPOXIA

Isolated strips of guinea-pig atrial myocardium were mounted in isomet ric myographs and electrically paced for measurements of myocardial co ntractile function. Levcromakalim, a K+ channel opener, completely inh ibited the contractile force in a concentration-dependent way (EC(50) = 15 mu M). Glibenclamide (3 mu M), a blocker of ATP-regulated K+ chan nels (K-ATP), caused a 5-fold rightward shift of the concentration-eff ect curve. Exposure of the atrial strips to hypoxia caused a time-depe ndent loss of contractility from 100% to a minimum level of 60% within 12 min. Levcromakalim (1 mu M, 3 mu M and 10 mu M) concentration-depe ndently enhanced the hypoxia-induced inhibition of contractile functio n whereas levcromakalim (0.01 mu M and 0.1 mu M) had no significant ef fect. In the presence of levcromakalim (10 mu M) hypoxia reduced the c ontractile force to 25%. Glibenclamide (3 mu M) totally antagonized th e enhancing effect of levcromakalim. When hypoxia was induced in gluco se-free Krebs solution with 2-deoxyglucose, the myocardial contractili ty was completely suppressed within 12 min. Glibenclamide by itself (3 mu M) 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-r egulated K+ channels accelerates and enhances the hypoxia-induced inhi bition of myocardial contractile function. This effect may possibly co ntribute to the mechanism by which K+ channel openers exert cardioprot ection. The results further suggest that mechanisms different from act ivation of K-ATP take a major part in the depressant mechanical respon se to hypoxia and glycolytic blockade in the guinea-pig atrial myocard ium.