Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo

Yada, Toyotaka; Shimokawa, Hiroaki; Hiramatsu, Osamu; Kajita, Tatsuya; Shigeto, Fumiyuki; Tanaka, Etsuro; Shinozaki, Yoshiro; Mori, Hiromu; Kiyooka, Takahiko; Katsura, Masashi; Ohkuma, Seitaro; Goto, Masami; Ogasawara, Yasuo; Kajiya, Fumihiko

doi:10.1016/j.jacc.2004.10.053

Cited by 51 publications

(39 citation statements)

References 43 publications

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“…However, the regulation of coronary vascular tone may be mediated, not only by NO, but also by the endothelium derived hyperpolarizing factor (EDHF) and adenosine (24). Yada et al have demonstrated that endogeneous H 2 O 2 , an EDHF, and rhokinase inhibition mediated coronary vasodilation to a greater extent in arterioles than in small arteries (7,8,24). In the present study, preservation of endotheliumdependent vasodilation by edaravone was noted to a greater extent in the small arteries (Fig.…”

Section: Edaravone Preserves Nitric Oxide and Enossupporting

confidence: 53%

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Edaravone Preserves Coronary Microvascular Endothelial Function After Ischemia/Reperfusion on the Beating Canine Heart In Vivo

et al. 2007

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Abstract. We examined whether edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, exerts its protective effect on coronary microvessels after ischemia / reperfusion (I/ R) in vivo. Ninety-minute coronary occlusion followed by reperfusion was performed in 16 open-chest dogs with and without edaravone administration. Coronary small artery (≥100 µm in size) and arteriolar (<100 µm) vasodilation, in the presence of endothelium-dependent (acetylcholine) or -independent (papaverine) vasodilators, was directly observed using intravital microscopy before and after I / R. I / R impaired microvascular vasodilation in response to acetylcholine, whereas administration of edaravone preserved the response in microvessels of both sizes, but to a greater extent in the coronary small arteries. No significant changes were noted with papaverine administration. In the edaravone group, the fluorescent intensity from reactive oxygen species (ROS) was lower, whereas nitric oxide (NO) intensity was higher relative to controls in the microvessels of the ischemic area. In conclusion, edaravone preserves coronary microvascular endothelial function after I / R in vivo. These effects, which were NOmediated, were attributed to the ROS scavenging properties of edaravone.

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Section: Edaravone Preserves Nitric Oxide and Enossupporting

confidence: 53%

“…4). Previous studies from our institution have also demonstrated a decrease in eNOS protein expression in ischemic myocardium following I / R (7,8). An in vitro study in HUVEC has shown that edaravone may increase eNOS expression via the inhibition of LDL oxidation (25).…”

Section: Edaravone Preserves Nitric Oxide and Enosmentioning

confidence: 69%

Edaravone Preserves Coronary Microvascular Endothelial Function After Ischemia/Reperfusion on the Beating Canine Heart In Vivo

et al. 2007

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“…Another ROCK inhibitor, fasudil, also decreased myocardial infarct size in rats and this cardioprotective effect was blocked by cotreatment with phosphatidylimositol 3-kinase inhibitors or the NOS inhibitor, L-NAME [90]. Similarly, hydroxyfasudil reduced myocardial infarct size in dogs after ischemiareperfusion injury, with an improved vasodilator response via preservation of the eNOS expression [98]. Moreover, treatment with fasudil improved LV remodeling and inhibited the inflammatory response in mice irrespective of infarction size or time of treatment [97].…”

Section: Rock In Heart Diseasesmentioning

confidence: 93%

ROCKs as therapeutic targets in cardiovascular diseases

Rikitake

Liao

2005

Expert Review of Cardiovascular Therapy

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There is growing evidence that Rho-kinases (ROCKs), the immediate downstream targets of the small guanosine triphosphate-binding protein Rho, may contribute to cardiovascular disease. ROCKs play a central role in diverse cellular functions such as smooth muscle contraction, stress fiber formation and cell migration and proliferation. Overactivity of ROCKs is observed in cerebral ischemia, coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis and atherosclerosis. ROCKs, therefore, may be an important and still relatively unexplored therapeutic target in cardiovascular disease. Recent experimental and clinical studies using ROCK inhibitors such as Y-27632 and fasudil have revealed a critical role of ROCKs in embryonic development, inflammation and oncogenesis. This review will focus on the potential role of ROCKs in cellular functions and discuss the prospects of ROCK inhibitors as emerging therapy for cardiovascular diseases. Keywords contraction; endothelium; hypertension; inflammation; leukocyte; remodeling; Rho-kinase; smooth muscleThe small guanosine triphosphate (GTP)-binding proteins belonging to the Rho family regulate various aspects of cell shape, motility, proliferation and apoptosis [1]. Rho-kinases (ROCKs), which were one of the first downstream effectors of Rho to be discovered [2-4], were found to mediate RhoA-induced actin cytoskeletal changes through effects on myosin light-chain (MLC) phosphorylation [5,6]. ROCKs are protein serine/threonine kinases that share 45-50% homology with other actin cytoskeletal kinases such as myotonic dystrophy kinase (DMPK), myotonic dystrophy-related cdc42-binding kinase (MRCK) and citron kinase [1]. ROCKs consist of an amino-terminal kinase domain, followed by a mid-coiled-coil-forming region containing a Rho-binding domain (RBD) and a carboxy-terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif (FIGURE 1). In mammalian systems, two ROCK isoforms have been identified. ROCK1, which is also known as ROKβ, and p160ROCK, which is located on chromosome 18 and encodes a 1354 amino acid protein [4,5]. ROCK2, which is also known as ROKα and sometimes confusingly called Rho-kinase, is located on chromosome 12 and contains 1388 amino acids [2,7,8]. ROCK1 and 2 share an overall 65% homology in amino acid sequence and 92% homology in their kinase domains

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“…Yada et al [19] reported that hydroxyfasudil caused significant coronary vasodilation of both small arteries and arterioles in a dose-dependent manner. In the present study, the CBF did not increase after administration of fasudil at a clinically relevant dose.…”

Section: Discussionmentioning

confidence: 99%

Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

Shibata

Use

Ureshino

et al. 2008

Cardiovasc Drugs Ther

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We assessed the effect of administration time for fasudil treatment of the stunned myocardium in 40 anesthetized open chest swine. All swine were subjected to 12 min ischemia followed by reperfusion to generate stunned myocardium. Group A (n = 11) received saline in place of fasudil both before ischemia and after reperfusion. Group B (n = 10) received 30 min intravenous fasudil at a rate of 13 µg/kg/min starting 45 min before ischemia and received saline after reperfusion.Groups C (n = 10) and D (n = 9) received saline before ischemia, and received fasudil at a rate of 13 µg/kg/min starting just before reperfusion in group C and 30 min after reperfusion in group D. In both groups, treatment lasted 30 min. Myocardial contractility was assessed by percent segment shortening (%SS). Three swine in group A, 2 swine in each of groups B and C, and one swine in group D had ventricular fibrillation or tachycardia after reperfusion and were excluded from further analysis.The changes of %SS from baseline at 90 min after reperfusion in groups B and C were 68 ± 8% and 75 ± 8%, respectively, which were significantly higher than in group A or D (47 ± 10% or 43 ± 8%). We conclude that fasudil administered before ischemia or Shibata et al. 4 just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium. (228 words)

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Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo

Abstract: Hydroxyfasudil exerts cardioprotective effects on coronary I/R injury in vivo, in which NO-mediated mechanism may be involved through preservation of eNOS expression.

Cited by 51 publications

References 43 publications

Edaravone Preserves Coronary Microvascular Endothelial Function After Ischemia/Reperfusion on the Beating Canine Heart In Vivo

Edaravone Preserves Coronary Microvascular Endothelial Function After Ischemia/Reperfusion on the Beating Canine Heart In Vivo

ROCKs as therapeutic targets in cardiovascular diseases

Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

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