Aims/hypothesis: Opening of ATP-sensitive potassium (K(ATP)) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K(ATP) channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K(ATP) channels in vivo.
Methods: Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K(ATP) channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K(ATP) blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion.
Results: With vehicle, epicardial MAP shortened by 44+/-9 ms during ischaemia. This effect was attenuated to 12+/-8 ms with troglitazone and 6+/-6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K(ATP) blockade. Intracoronary levcromakalim shortened MAP by 38+/-10 ms, an effect attenuated to 12+/-8, 13+/-4 and 9+/-5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K(ATP) blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K(ATP) blockade promotes ischaemic ventricular fibrillation in this model.
Conclusions/interpretation: Thiazolidinedione drugs block cardiac K(ATP) channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633423 | PMC |
| http://dx.doi.org/10.1007/s00125-008-0924-0 | DOI Listing |
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