KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo.
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.


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.


CONCLUSIONS
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.
Centre for Clinical Pharmacology, University College London, London, United Kingdom. M.Broadhead@ich.ucl.ac.uk.
M W
MW
Broadhead
R K
RK
Kharbanda
M J
MJ
Peters
R J
RJ
MacAllister
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D003981:Diazoxide / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005542:Forearm / Q000098:blood supply; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D019194:Ischemic Preconditioning; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D015290:Second Messenger Systems; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; D005996:Nitroglycerin; D000109:Acetylcholine; D003981:Diazoxide; D011188:Potassium; D005905:Glyburide