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Differential Class III and glibenclamide effects on action potential duration in guinea‐pig papillary muscle during normoxia and hypoxia/ischaemia
Author(s) -
MacKenzie I.,
Saville V.L.,
Waterfall J.F.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13843.x
Subject(s) - hypoxia (environmental) , guinea pig , glibenclamide , ischemia , papillary muscle , medicine , anesthesia , chemistry , neuroscience , pharmacology , cardiology , endocrinology , biology , oxygen , diabetes mellitus , organic chemistry
1 Microelectrode recording techniques were used to study the effects of several potassium channel blockers which are considered to be Class III antiarrhythmic compounds. The effects of (+)‐sotalol, UK‐66,914, UK‐68,798 and E‐4031 on action potential duration (APD) were determined in guinea‐pig isolated papillary muscles. The compounds were evaluated under normoxic or hypoxic/ischaemic conditions at 36.5°C and compared to glibenclamide, which is considered to be a blocker of ATP‐dependent potassium channels. Prolongation of action potential duration at 90% repolarization (APD 90 ) was taken as an indirect measure of potassium channel blockade. 2 Under normoxic conditions, the Class III compounds prolonged APD in a concentration‐dependent manner. According to EC 15 values, the order of potency of the Class III compounds was found to be UK‐68,798 > E‐4031 > UK‐66,914 > (+)‐sotalol. Glibenclamide did not significantly prolong APD 90 under normoxic conditions. 3 Perfusion with an experimental hypoxic or ischaemic bathing solution produced qualitatively similar effects on action potentials. Over a period of 20–25 min in either of the experimental solutions, there was a small decrease in action potential amplitude (APA) and a prominent shortening of APD. The ischaemic solution also depolarized the resting membrane potential by about 15 mV. 4 (+)‐Sotalol and UK‐66,914 did not reverse the shortening of APD induced by perfusion with hypoxic Krebs solution. High concentrations of glibenclamide (10 μ m ) and UK‐68,798 (30 and 60 μ m ) 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‐4031 (10 μ m , n = 7) produced small, but significant, increases in the APD90 (11 ± 3 ms after 20 min) which were not clearly time‐dependent (14 ± 4 ms after 30 min). UK‐68,798 (10 μ m ) also produced a small, but insignificant, increase in APD 90 (12 ± 6 ms at 20 min, n = 4). Higher concentrations of UK‐68,798 (30 and 60 μ m , n = 4) did not produce a consistently significant increase in APD 90 during ischaemia: significance was only attained after 20 min in the presence of 60 μ m UK‐68,798 (24 ± 12 ms). However, in marked contrast to the effects of the Class III compounds, glibenclamide (10 μ m ) produced large time‐dependent increases in ischaemic APD 90 (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 microelectrode data suggest that blockers of ATP‐dependent potassium channels, such as glibenclamide, might prove to be more effective than Class III compounds against ischaemia‐induced shortening of cardiac action potentials.