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(Circulation. 2004;110:2077-2082.)
© 2004 American Heart Association, Inc.

Arrhythmia/Electrophysiology

K_ATP Channel Activation Induces Ischemic Preconditioning of the Endothelium in Humans In Vivo

From the Centre for Clinical Pharmacology (M.W.B., R.J.M.), University College London, London, United Kingdom; Division of Cardiovascular Medicine (R.K.K.), Addenbrookes Hospital, Cambridge, United Kingdom; and Critical Care Group (M.W.B., M.J.P.), Portex Unit, Institute of Child Health, London, United Kingdom.

Correspondence to M.W. Broadhead, Centre for Clinical Pharmacology, BHF Laboratories, The Rayne Building, 5 University St, London WC1E 6JJ, England. E-mail M.Broadhead{at}ich.ucl.ac.uk

Received January 15, 2004; de novo received May 20, 2004; accepted June 22, 2004.

Background— Endothelial dysfunction contributes to ischemia-reperfusion injury (IRI) and is reduced by ischemic preconditioning (IPC). IPC may involve activation of ATP-sensitive potassium channels (K_ATP). We determined whether modulation of K_ATP channels occurs in endothelial IPC in humans.

Methods and Results— IRI of the forearm was induced by inflating a blood pressure cuff to 200 mm Hg for 20 minutes in healthy volunteers. K_ATP activation was modulated by intra-arterial glibenclamide (blocker) and diazoxide (opener). Endothelial function (response to intra-arterial acetylcholine) was assessed with forearm plethysmography before and after (1) 15-minute reperfusion, (2) IRI preceded by IPC (3 five-minute periods of ischemia), (3) IRI preceded by IPC with glibenclamide, (4) IPC followed by glibenclamide before IRI, (5) IRI preceded by diazoxide, and (6) IRI preceded by coinfusion of glibenclamide with diazoxide. IRI caused endothelial dysfunction (P=0.002), which IPC prevented (P=0.40). Glibenclamide abolished IPC when given contemporaneously with (P=0.003) or during IRI (P=0.0005). Diazoxide prevented endothelial dysfunction after IRI (P=0.68) but not when coinfused with glibenclamide.

Conclusion— Glibenclamide abolishes and diazoxide mimics endothelial IPC in humans. The time course of the effect of glibenclamide suggests involvement of K_ATP channels as effectors of endothelial IPC in vivo. These data may have implications for understanding the therapeutic role of agents that modulate K_ATP channel function.

Key Words: ischemia • reperfusion • potassium channels • ischemic preconditioning

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