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Rosiglitazone inhibits vascular K ATP channels and coronary vasodilation produced by isoprenaline
Author(s) -
Yu Lei,
Jin Xin,
Yang Yang,
Cui Ningren,
Jiang Chun
Publication year - 2011
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.1476-5381.2011.01539.x
Subject(s) - isoprenaline , vasodilation , cardiology , medicine , chemistry , stimulation
BACKGROUND AND PURPOSE Rosiglitazone is an anti‐diabetic drug improving insulin sensitivity and glucose uptake in skeletal muscle and adipose tissues. However, several recent clinical trials suggest that rosiglitazone can increase the risk of cardiovascular ischaemia, although other studies failed to show such risks. Therefore, the effects of rosiglitazone on the coronary circulation and any potential vascular targets need to be elucidated. Here, we show that the vascular isoform of the ATP‐sensitive K + (K ATP ) channel is inhibited by rosiglitazone, impairing physiological regulation of the coronary circulation. EXPERIMENTAL APPROACH The K IR 6.1/SUR2B channel was expressed in HEK293 cells and studied in whole‐cell and inside‐out patch configurations. The Langendorff heart preparation was used to evaluate rosiglitazone in the coronary circulation of wild‐type (WT) and K IR 6.1‐null ( Kcnj8 −/− ) mice. KEY RESULTS K IR 6.1/SUR2B channels in HEK cells were inhibited by rosiglitazone in a membrane‐delimited manner. This effect was markedly enhanced by sub‐micromolar concentrations of glibenclamide and the IC 50 for rosiglitazone fell to 2µM, a therapeutically achievable concentration. In the Langendorff heart preparation rosiglitazone inhibited, concentration‐dependently, the coronary vasodilation induced by isoprenaline, without affecting basal coronary tone. Effects of rosiglitazone on coronary perfusion were attenuated by more than 50% in the Kcnj8 −/− mice, supporting the involvement of K ATP channels in this effect of rosiglitazone on the coronary circulation. CONCLUSIONS AND IMPLICATIONS These results indicate that the vascular K ATP channel is one of the targets of rosiglitazone action, through which this drug may compromise coronary responses to circulating vasodilators and perhaps also to metabolic stress.