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

Toyotaka Yada, MD, PhD^*,*, Hiroaki Shimokawa, MD, PhD, Osamu Hiramatsu, PhD^*, Tatsuya Kajita, MD, PhD^*, Fumiyuki Shigeto, MD, PhD^*, Etsuro Tanaka, MD, PhD, Yoshiro Shinozaki, BS, Hidezo Mori, MD, PhD^||, Takahiko Kiyooka, MD^#, Masashi Katsura, PhD^¶, Seitaro Ohkuma, MD, PhD^¶, Masami Goto, MD, PhD^*, Yasuo Ogasawara, PhD^* and Fumihiko Kajiya, MD, PhD^#

^* Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki, Japan
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, Japan
Department of Physiology, Tokai University School of Medicine, Isehara, Japan
^|| Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Japan
^¶ Department of Pharmacology, Kawasaki Medical School, Kurashiki, Japan
^# Department of Cardiovascular Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Manuscript received September 2, 2004; revised manuscript received October 1, 2004, accepted October 18, 2004.

^* Reprint requests and correspondence: Dr. Toyotaka Yada, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan (Email: yada{at}me.kawasaki-m.ac.jp).

OBJECTIVES: We examined whether hydroxyfasudil, a specific Rho-kinase inhibitor, exerts cardioprotective effect on coronary ischemia/reperfusion (I/R) injury and, if so, whether nitric oxide (NO) is involved.

BACKGROUND: Recent studies have demonstrated that Rho-kinase is substantially involved in the pathogenesis of cardiovascular diseases; however, it remains to be examined whether it is also involved in ischemia/reperfusion (I/R) injury.

METHODS: Canine subepicardial small arteries (SA, 100 µm) and arterioles (A, <100 µm) were observed by a charge-coupled device intravital microscope during I/R. Coronary vascular responses to endothelium-dependent (acetylcholine, intracoronary [IC]) and -independent (papaverine, IC) vasodilators were examined after I/R under the following four conditions: control (n = 7), NO synthase inhibitor alone (N^G-monomethl-L-arginine [L-NMMA], IC, n = 4), hydroxyfasudil alone (IC, n = 7), and hydroxyfasudil plus L-NMMA (n = 7).

RESULTS: Hydroxyfasudil significantly attenuated serotonin (IC)-induced vasoconstriction of SA (–7 ± 1% vs. 2 ± 1%, p < 0.01). Coronary I/R significantly impaired coronary vasodilation to acetylcholine after I/R (SA, p < 0.05; and A, p < 0.01 vs. before I/R) and L-NMMA further reduced the vasodilation, whereas hydroxyfasudil completely preserved the responses. The vasoconstriction by L-NMMA after I/R was significantly improved by hydroxyfasudil in both-sized arteries (both p < 0.01). Expression of endothelial nitric oxide synthase (eNOS) protein in the ischemic endocardium of left anterior descending coronary artery area (as determined by Western blotting) significantly decreased (79 ± 4%) compared with the nonischemic endocardium of LCX area (100 ± 7%), which was improved by hydroxyfasudil (105 ± 6%, p < 0.01). Hydroxyfasudil significantly reduced myocardial infarct size, and hydroxyfasudil with L-NMMA also reduced the infarct size compared with L-NMMA alone.

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

Abbreviations and Acronyms   I/R = ischemia-reperfusion   LAD = left anterior descending coronary artery   LCX = left circumflex artery   NO = nitric oxide

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