Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of Rho-kinase inhibitor, fasudil, and of a more specific Rho-kinase inhibitor, hydroxyfasudil, on pacing-induced myocardial ischaemia were determined in anaesthetized open-chest dogs. 2. The dogs were subjected to left anterior descending coronary artery (LAD) stenosis producing a sufficient ischaemia as measured by ST-segment depression on electrocardiograms only when the hearts were paced 60 beats min(-1) above the baseline. After a recovery (nonpacing) period, drugs or saline were infused intravenously over 30 min. The animals were again subjected to 5 min of pacing 25 min after the initiation of the treatment. 3. Hydroxyfasudil (0.1 and 0.3 mg kg(-1)) and fasudil (0.3 mg kg(-1)) suppressed the ST-segment depression. Hydroxyfasudil and fasudil also increased the regional blood flow of the LAD perfused endomyocardium region in the canine model of effort angina. 4. To determine the flow profile for hydroxyfasudil in dogs, blood flow in three vascular beds was measured. Hydroxyfasudil (0.3 mg kg(-1) for 30 min) significantly increased coronary blood flow and vertebral blood flow, without significantly changing the femoral blood flow. 5. Hydroxyfasudil had no inotropic or chronotropic effect on the isolated hearts of guinea-pigs. Hydroxyfasudil (2 mg kg(-1) for 20 min) did not affect the PR or QTc interval in anaesthetized dogs. 6. Inhibition of Rho-kinase appears to protect myocardium subjected to pacing-induced ischaemia through the increase in the regional myocardial blood flow. Hydroxyfasudil may be categorized as a novel type of anti-anginal drug, without any inotropic or chronotropic effects.
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PMID:Antianginal effects of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina. 1173 49

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that the Rho/Rho-kinase-mediated pathway plays an important role in various cellular functions, not only in vascular smooth muscle contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of arteriosclerosis/atherosclerosis. Indeed, animal experiments have demonstrated that Rho-kinase inhibitors effectively suppress coronary artery spasm and that long-term inhibition of Rho-kinase inhibits the development of coronary arteriosclerotic lesions and even causes regression of coronary vascular lesions in vivo. Recent clinical studies also have demonstrated the inhibitory effect of a Rho-kinase inhibitor on coronary artery spasm in patients with vasospastic angina and on exercise-induced myocardial ischemia in patients with stable effort angina with adequate safety. It is possible that Rho-kinase is also involved in the pathogenesis of other forms of cardiovascular diseases. Thus, Rho-kinase could be regarded as a novel therapeutic target in treatment of cardiovascular diseases.
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PMID:Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. 1186 9

The aim of this study was to develop a new model of vasopressin-induced chronic myocardial damage based on sustained ST-segment depression in electrocardiogram (ECG) with progression of myocardial fibrosis in rats. Furthermore, using this model, we examined the prophylactic potential of fasudil, a Rho-kinase inhibitor, against myocardial damage induced by vasopressin. In 10-week old male Donryu rats, intravenous administration of arginine vasopressin (0.5 iu/kg) induced significant ST-segment depression. Two days and one week after the administration of vasopressin, ST-segment depression was -0.19 +/- 0.02 and -0.14 +/- 0.02 mV, respectively. Fasudil (10 and 30 mg/kg, p.o.) significantly attenuated the ST-segment depression induced by vasopressin. One week after the administration of vasopressin, the percent area of myocardial fibrosis in control animals (0.42 +/- 0.11%, p < 0.01) was significantly greater than that in normal animals (0.05 +/- 0.01%). Fasudil (10 and 30 mg/kg) significantly prevented the development of the fibrosis. We present a new model of chronic myocardial damage based on sustained ST-segment depression with progression of myocardial fibrosis in rats, and suggest that this model may be useful to investigate the treatment of chronic angina. Inhibition of Rho-kinase is efficacious in preventing the ECG change and development of fibrosis induced by vasopressin in this model.
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PMID:Effects of Rho-kinase inhibitor on vasopressin-induced chronic myocardial damage in rats. 1240 49

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.
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PMID:Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. 1240 84

The designation of atherosclerosis as a chronic inflammatory process represents an interesting paradigmatic shift for cardiologists. The plasma concentrations of interleukin-6 and its hepatic byproduct, C-reactive protein, may reflect the intensity of occult plaque inflammation and the vulnerability to rupture. Monocyte chemoattractant protein-1 and interleukin-8 play a crucial role in initiating atherosclerosis by recruiting monocytes/macrophages to the vessel wall, which promotes atherosclerotic lesions and plaque vulnerability. In addition, circulating levels of these proinflammatory cytokines increase in patients with acute myocardial infarction and unstable angina, but not in those with stable angina. Also, the plasma concentrations of these cytokines increase after percutaneous coronary intervention, causing late restenosis after the procedure. Angiotensin II and other atherogenic factors induce these cytokines in the cardiovascular tissues through the activation of transcription factors, such as nuclear factor-kappaB or peroxisome proliferator-activated receptors. Conversely, HMG-CoA reductase inhibitors (statins) can potently inhibit these proinflammatory factors in the vessels. A small GTP-binding protein, Rho, may be a key molecule to explain the anti-inflammatory effects of statins. Interleukin-10 also exerts anti-inflammatory effects on the cardiovascular tissues, possibly by deactivating proinflammatory cytokines and inducible nitric oxide synthase. Gene therapy using interleukin-10 may be a promising means for untreatable or complicated cases of cardiovascular diseases. Thus, therapeutic modulations of these inflammatory cytokines may be useful in the prevention of atherosclerosis and future cardiovascular events.
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PMID:Inflammatory cytokines and cardiovascular disease. 1456 Nov 60

An 86-year-old woman was admitted with unstable angina pectoris. Plain old balloon angioplasty (POBA) was performed for 90% stenosis at segment 7 of the left coronary artery with concomitant treatment with nitrate, calcium antagonists, and nicorandil. Five days after POBA, she again suffered chest pain at rest with ST depression by electrocardiography, despite increased doses of calcium-antagonist and nicorandil. Coronary arteriography showed no evidence of restenosis (50%) at the POBA site. The involvement of coronary artery spasm was considered and intravenous treatment with a Rho-kinase inhibitor, fasudil, was started, which resulted in disappearance of the anginal attacks. She refused to continue the fasudil treatment on day 5, which resulted in reappearance of anginal attacks. Third coronary angiography showed a 90% restenosis at POBA site and percutaneous coronary intervention was again performed. This case suggests that a Rho-kinase inhibitor is potentially effective to prevent anginal attacks in spastic angina.
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PMID:[Inhibition of Rho-kinase by fasudil preventing anginal attacks associated with spastic angina: a case report]. 1553 47

Rho-kinase is a signaling molecule that occurs downstream of the small GTPase Rho, which mediates various cellular functions. The Rho/Rho-kinase pathway plays an important role in pathophysiology and progression of various cardiovascular diseases such as hypertension, coronary vasospasm, angina pectoris, and restenosis after percutaneous coronary intervention, all of which are related to arteriosclerosis/atherosclerosis changes of the vasculature. Activation of the Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes of the blood vessels and affects cardiac myocytes. Evidence from in vitro and in vivo studies suggests that Rho-kinase inhibitors have beneficial effects on cardiovascular diseases, particularly arteriosclerosis and coronary vasospasm. Furthermore, activation of the Rho/Rho-kinase pathway contributes to blood pressure regulation via the central sympathetic nervous system. There is evidence to suggest that Rho-kinase is involved in angiotensin II-induced cardiac hypertrophy and endothelial dysfunction, and preliminary data indicate that inhibition of Rho-kinase may be beneficial in vascular disorders such as pulmonary arterial hypertension and erectile dysfunction. Fasudil is currently the only Rho-kinase inhibitor available for clinical use and it is approved in Japan for the prevention of vasospasm in patients with subarachnoid hemorrhage. Emerging clinical data have shown that oral fasudil 80 mg three times daily is effective in preventing myocardial ischemia in patients with stable angina pectoris. Rho-kinase represents a new target for the management of cardiovascular diseases and further studies are needed to define the therapeutic potential of Rho-kinase inhibitors.
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PMID:Therapeutic potential of rho-kinase inhibitors in cardiovascular diseases. 1563 36

Coronary vasospasm is currently considered to be an exaggerated contractile nonspecific response of the vascular smooth muscle in the large coronary artery to various agonists or stimulation, that is established after the process of inflammation and fibrocellular proliferation. Endothelial dysfunction with reduced nitric oxide bioavailability has been reported in angiographically normal coronary arteries in Japanese patients with coronary spastic angina. Recently, several interesting findings concerning the exact mechanism of calcium hypersensitivity of spastic vascular smooth muscle have been reported. In animal models with coronary spasm Rho-kinase is upregulated at the spastic site and plays a key role in inducing vascular smooth muscle hypercontraction by inhibiting myosin light chain phosphatase, resulting in enhancement of its phosphorylation. Also, oxidative stress has been given attention as an important mediator of the spastic conversion of vascular smooth muscle cell "phenotype." The incidence of coronary spastic angina in the Japanese population is reported to be remarkably high compared with that in Caucasians. Clinical and pathophysiological differences between Japanese and Caucasian patients with respect to coronary vasospasm are characterized by a lower prevalence of fixed coronary artery stenoses and diffuse coronary hyperreactivity in the Japanese patients. Recently, several distinct characteristics have been recognized to be associated with coronary vasospasm in studies analyzing data obtained from Japanese patients. In the present review, we will discuss our point of view on the mechanisms and predisposing factors in coronary vasospasm. Predisposing factors include smoking, lipid metabolic disorders, and gene expression, all of which may be interrelated issues.
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PMID:Recent insights into the mechanisms, predisposing factors, and racial differences of coronary vasospasm. 1570 Jan 95

Resistance arteries are able to adapt to physiological and pathophysiological stimuli to maintain adequate perfusion according to the metabolic demand of the tissue. Although vasomotor control allows rapid adaptation of lumen diameter, vascular remodeling constitutes an active process that occurs in response to long-term alterations of hemodynamic parameters. Unfortunately, this initially adaptive process contributes to the pathology of vascular diseases. Recent studies have demonstrated the participation of Rho protein signaling pathways in several cardiovascular pathologies including hypertension, coronary artery spasm, effort angina, atherosclerosis, and restenosis. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration, and proliferation associated with arterial diseases. The present review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in resistance artery remodeling, more particularly in relation to hypertension.
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PMID:RhoA and resistance artery remodeling. 1570 42

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.
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PMID:Rho-kinase is an important therapeutic target in cardiovascular medicine. 1600 41


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