Vasodilatory Effect of Subsequent Administration of Fasudil, a Rho-Kinase Inhibitor, Surpasses That of Nitroglycerin at the Concentric Coronary Stenosis in Patients With Stable Angina Pectoris

Abstract

oronary arteries exert a vasomotor action that responds to numerous stimuli such as neurohormonal factors, endothelium-derived substances, and artificially administered vasoactive agents in a sensitive manner. 1,2 Indeed, intact epicardial coronary arteries dilate promptly after the administration of nitrates or other kinds of vasodilators. 3 In contrast, it remains controversial 4-8 as to whether the coronary atherosclerotic site responds to vasodilatory agents; this continues to be an important topic in terms of the treatment of stable angina pectoris (SAP). In clinical situations, Kaski et al 6 and Yamagishi et al 8 reported that the vasodilatory potential at the coronary atherosclerotic site was impaired. In contrast, McPherson et al suggested in their report 7 that the coronary atherosclerotic site had a vasodilating ability. It should be emphasized, however, that these clinical studies only adopted nitrates for the evaluation of coronary vasomotion at the site of atherosclerotic lesions. Therefore, other vasodilators than nitrates should be used to more accurately assess the vasodilatory potential at atherosclerotic lesions.It has recently been reported that the Rho/Rho-kinase mediated pathway (Rho-kinase pathway) is involved in the pathogenesis of various cardiovascular disorders. 9-16 Rhokinase is one of the downstream effectors of small GTPase Rho, and it plays a pivotal role in diverse cellular functions, such as actin cytoskeleton organization, 17,18 cell adhesion and motility, 19 cytokinesis, 20 gene expression, 21 and smooth muscle contraction. 22 In clinical situations, the Rho-kinase pathway contributes to the occurrence of both epicardial 23 and microvascular 24 coronary artery spasm and the augmentation of peripheral vascular resistance in both patients with hypertension 25 and normotensive current smokers. 26 These findings suggest that the Rho-kinase pathway regulates the vasomotion of arteries suffering from pathological conditions. It remains unclear, however, as to whether this pathway is also involved in the regulation of coronary vasomotion at the atherosclerotic site, which is one of the most prevalent diseased states in the arterial wall.We therefore hypothesized that the degree of coronary vasodilation at the atherosclerotic site with pharmacological inhibition of the Rho-kinase pathway was more potent than that with nitrates. In the present study, to confirm this hypothesis, we compared the vasodilatory effect of nitroglycerin (NTG) with the subsequent administration of fasudil, a Rho-kinase inhibitor, at a site of concentric coronary stenosis, which was considered to reflect the whole circumferential atherosclerosis in the arterial wall, 27 in patients with SAP. Background Recent studies have suggested that the Rho/Rho-kinase mediated pathway (Rho-kinase pathway) regulates the vasomotion of arteries in pathological conditions. However, it remains unclear regarding whether this pathway regulates the coronary vasomotion of atherosclerotic lesions. Methods and ResultsThe coronary diamet...

Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases

“…Fasudil inhibits coronary vasospasm in patients with unstable angina pectoris [69] and for the treatment of cerebral vasospasm after subarachnoid hemorrhage [70]. The vasodilatory effect of fasudil is more potent than that of nitroglycerin [71] and has been shown to further dilate segments of vasospastic coronary artery that have already been pre-treated with nitroglycerin [72]. These findings support the potential of fasudil as a novel therapeutic agent for coronary and cerebral vasospasm.…”

Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats

“…ROCK inhibitors have been used clinically in the treatment of both hypertension and angina [27,28]. In fact, recently the vasodilatory effect of the ROCK inhibitor, fasudil, was reported to be greater than that of nitroglycerin at sites of coronary stenosis in angina patients [29]. Because diabetic cardiomyopathy frequently coexists and synergistically interacts with coronary heart disease and hypertension, it would be ideal to have a drug that treats these conditions concurrently.…”

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

“…ROCK inhibitors are currently in use or in human trials for a variety of CNS and non-CNS conditions [37,[79][80][81][82][83][84][85][86][87][88]. Application of ROCK inhibitors in vivo may affect NPC cell-cell association and promote aberrant NPC migration, leading to altered NPC signal transduction.…”