Repetition of ischemic preconditioning augments endothelium-dependent vasodilation in humans: role of endothelium-derived nitric oxide and endothelial progenitor cells.

BACKGROUND Several studies have shown that both early and late effects of ischemic preconditioning (IPC) protect against myocardial injury after ischemic reperfusion. METHODS AND RESULTS The purpose of this study was to evaluate the late effects of IPC on endothelial function in humans. Late phase of IPC was induced by upper limb ischemia (cuff inflation of over 200 mm Hg for 5 minutes) 6 times a day for 1 month. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh) and to sodium nitroprusside (SNP) before and after IPC stimulus in 30 young healthy men. FBF was measured using a strain-gauge plethysmograph. The IPC stimulus significantly increased plasma concentration of vascular endothelial growth factor (VEGF), circulating level of endothelial progenitor cells (EPCs), and FBF responses to ACh, but these did not change in the control group. The FBF responses to SNP were similar before and after the IPC stimulus. Infusion of N(G)-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely eliminated the IPC stimulus-induced augmentation of FBF responses to ACh. In the contralateral arms of subjects that received the IPC stimulus, FBF responses to ACh did not change, but levels of VEGF and circulating EPCs increased. CONCLUSIONS These findings suggest that repetition of late IPC stimulus augments endothelium-dependent vasodilation in humans through increases in nitric oxide production and number of EPCs under a local condition. Repetition of IPC stimulus may be a simple, safe, and feasible therapeutic technique for endothelial protection of peripheral vessels.