Ischemic heart disease is the leading cause of morbidity and mortality in a worldwide epidemic. Myocardial ischemia is characterized by an imbalance between myocardial oxygen supply and demand, causing cardiac dysfunction, arrhythmias, myocardial infarction, and sudden death. Various clinical ischemic manifestations are caused by obstruction of coronary blood flow by coronary plaques, thrombosis, and/or hyperconstriction/vasospasm of epicardial and microvascular coronary arteries, in which gender difference also is involved due in part to estrogen hormonal state. The coronary circulation matches blood flow with oxygen requirements by coordinating the resistances within microvasculature, where the endothelium plays an important role by liberating several vasodilator substances. The impaired endothelial regulation is involved in the pathogenesis of a wide variety of cardiovascular diseases and therefore is an important therapeutic target. Activation of Rho-kinase pathway is involved in the pathogenesis of both endothelial dysfunction and vascular smooth muscle hypercontraction and also should be an important therapeutic target. (C) 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.