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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1403.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Repetition of Ischemic Preconditioning Augments Endothelium-Dependent Vasodilation in Humans

Role of Endothelium-Derived Nitric Oxide and Endothelial Progenitor Cells

Masashi Kimura; Keiko Ueda; Chikara Goto; Daisuke Jitsuiki; Kenji Nishioka; Takashi Umemura; Kensuke Noma; Masao Yoshizumi; Kazuaki Chayama; Yukihito Higashi

From the Department of Medicine and Molecular Science (M.K., K.U., K.C.) and the Department of Cardiovascular Physiology and Medicine (C.G., D.J., K.N., T.U., M.Y., Y.H.), Hiroshima University Graduate School of Biomedical Sciences, Japan.

Correspondence to Yukihito Higashi, MD, PhD, FAHA, Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Mimami-ku, Hiroshima 734-8551, Japan. E-mail yhigashi{at}hiroshima-u.ac.jp

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 cotralateral 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.

We evaluated forearm blood flow responses to acetylcholine and to sodium nitroprusside before and after ischemic preconditioning (IPC) stimulus in 30 young healthy men. Repetition of late IPC stimulus augments endothelium-dependent vasodilation in humans through increases in nitric oxide production and number of endothelial progenitor cells under a local condition.

Key Words: preconditioning • endothelial function • nitric oxide • vascular endothelial growth factor • endothelial progenitor cells