DIFFERENTIAL CLASS-III AND GLIBENCLAMIDE EFFECTS ON ACTION-POTENTIAL DURATION IN GUINEA-PIG PAPILLARY-MUSCLE DURING NORMOXIA AND HYPOXIA-ISCHEMIA

1 Microelectrode recording techniques were used to study the effects o f several potassium channel blockers which are considered to be Class III antiarrhythmic compounds. The effects of (+)-sotalol, UK-66,914, U K-68,798 and E-4031 on action potential duration (APD) were determined in guinea-pig isolated papillary muscles. The compounds were evaluate d under normoxic or hypoxic/ischaemic conditions at 36.5-degrees-C and compared to glibenclamide, which is considered to be a blocker of ATP -dependent potassium channels. Prolongation of action potential durati on at 90% repolarization (APD90) was taken as an indirect measure of p otassium channel blockade. 2 Under normoxic conditions, the Class III compounds prolonged APD in a concentration-dependent manner. According to EC15 values, the order of potency of the Class III compounds was f ound to be UK-68,798 > E-4031 > UK-66,914 > (+)-sotalol. Glibenclamide did not significantly prolong APD90 under normoxic conditions. 3 Perf usion with an experimental hypoxic or ischaemic bathing solution produ ced qualitatively similar effects on action potentials. Over a period of 20-25 min in either of the experimental solutions, there was a smal l decrease in action potential amplitude (APA) and a prominent shorten ing of APD. The ischaemic solution also depolarized the resting membra ne potential by about 15 mV. 4 (+)-Sotalol and UK-66,914 did not rever se the shortening of APD induced by perfusion with hypoxic Krebs solut ion. High concentrations of glibenclamide (10 muM) and UK-68,798 (30 a nd 60 muM) partially reversed the hypoxia-shortened APD. Glibenclamide was more potent and exhibited a greater time-dependent action than UK -68,798. 5 During experimental ischaemia, the Class III compound E-403 1 (10 muM, n = 7) produced small, but significant, increases in the AP D90 (11 +/- 3 ms after 20 min) which were not clearly time-dependent ( 14 +/- 4 ms after 30 min). UK-68,798 (10 muM) also produced a small, b ut insignificant, increase in APD90 (12 +/- 6 ms at 20 min, n = 4). Hi gher concentrations of UK-68,798 (30 and 60 muM, n = 4) did not produc e a consistently significant increase in APD90 during ischaemia: signi ficance was only attained after 20 min in the presence of 60 muM UK-68 ,798 (24 +/- 12 ms). However, in marked contrast to the effects of the Class III compounds, glibenclamide (10 muM) produced large time-depen dent increases in ischaemic APD90 (34 +/- 11 ms at 7 min, n = 9) which were significant 15 min or more after drug addition (52 +/- 12 ms at 20 min, n = 7; 74 +/- 5 ms at 30 min, n = 6). 6 The present microelect rode data suggest that blockers of ATP-dependent potassium channels, s uch as glibenclamide, might prove to be more effective than Class III compounds against ischaemia-induced shortening of cardiac action poten tials.