EFFECTS OF POTASSIUM CHANNEL BLOCKERS ON THE NEGATIVE INOTROPIC RESPONSES INDUCED BY CROMAKALIM AND PINACIDIL IN GUINEA-PIG ATRIUM

The K+ channel openers cromakalim and pinacidil induced a concentration-dependent reduction in atrial contraction force with EC50 values of 25 +/- 2 and 37 +/- 2-mu-mol/l, respectively. This depressant effect was antagonised by 50-mu-mol/l tacrine which displaced the concentration-response curves of cromakalim and pinacidil to the right. The respective DR50 values were 3.8 and 2.3. Increasing the tacrine concentration (100 and 500-mu-mol/l) produced no additional effect on the concentration-response relationships. Addition of 1-mu-mol/l atropine enhanced the antagonism due to tacrine by increasing the DR50 value from 3.8 to 6.5 for cromakalim and from 2.3 to 5.2 for pinacidil. Glibenclamide, an ATP-sensitive K+ channel blocker, competitively inhibited the negative inotropic effects of cromakalim and pinacidil. The respective dissociation constants for glibenclamide against cromakalim and pinacidil were 0.57 and 0.35-mu-mol/l. Neither apamin nor variation in external Ca2+ concentration affected the negative inotropic effects of the K+ channel openers. It was suggested that the mechanical effects of cromakalim and pinacidil are mediated through the ATP-sensitive K+ channels in the heart.