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Rosiglitazone inhibits vascular KATP channels and coronary vasodilation produced by isoprenaline.

Abstract：

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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Yu L,Jin X,Yang Y,Cui N,Jiang C

doi

10.1111/j.1476-5381.2011.01539.x

subject

Has Abstract

pub_date

2011-12-01 00:00:00

pages

2064-72

issue

eissn

0007-1188

issn

1476-5381

journal_volume

164

pub_type

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Rosiglitazone inhibits vascular KATP channels and coronary vasodilation produced by isoprenaline.