Postconditioning protects against human endothelial ischaemiareperfusion injury via subtype-specific K ATP channel activation and is mimicked by inhibition of the mitochondrial permeability transition pore

Abstract

Aims Intermittent early reperfusion (ischaemic postconditioning; PostC) reduces ischaemiareperfusion (IR) injury. Using an in vivo model of endothelial IR injury in humans, we sought to determine the role of KATP channels in PostC and whether inhibition of the mitochondrial permeability transition pore (mPTP) at the onset of reperfusion protected against endothelial IR injury. Methods and resultsEndothelial function (EF) in healthy volunteers was assessed using vascular ultrasound to measure the percentage increase in the diameter of the brachial artery in response to reactive hyperaemia [flow-mediated dilatation (FMD)]. In resistance vessels, venous occlusion plethysmography was used to measure the dilator response to acetylcholine (ACh) [area under ACh doseresponse curve (ACh AUC)]. Measurements were made before and after IR injury. Ischaemic postconditioning consisted of three 10 s cycles of alternating ischaemia and reperfusion in the first minute of reperfusion. Oral glibenclamide and glimepiride were used to determine the role of KATP channel subtypes in PostC. Intra-arterial cyclosporine was used to determine the role of mPTP in endothelial IR injury. Ischaemiareperfusion reduced EF in the brachial artery (FMD 7.1 ± 0.9% pre-IR, 2.8 ± 0.4% post-IR; P < 0.001) and resistance vessels [ACh AUC (×10 4) 2.1 ± 0.4 pre-IR, 1.5 ± 0.2 post-IR; P < 0.05]. Ischaemic postconditioning preserved EF in the brachial artery [FMD 6.8 ± 0.9% (P < 0.001 vs. post-IR)] and resistance vessels [ACh AUC (×10 4) 1.9 ± 0.2% (P < 0.001 vs. post-IR)]. Protection by PostC was abolished by glibenclamide in the brachial artery [FMD 3.3 ± 0.2 (P < 0.001 vs. post-IR PostC)] and in resistance vessels [ACh AUC (×10 4) 1.1 ± 0.2 (P < 0.001 vs. post-IR PostC)], whereas glimepiride had no effect. Cyclosporine preserved EF after IR injury in the resistance vessels [ACh AUC (×10 4) 1.4 ± 0.2 post-IR vs. 2.2 ± 0.3 post-IR cyclosporine; P < 0.05]. Conclusion Protection by PostC against endothelial IR injury in humans depends on KATP channel activation and is mimicked by inhibition of the mPTP at reperfusion. © The Author 2011.