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EXPERIMENTAL STUDY

Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart

Hisakazu Ogita, MD^*, Koichi Node, MD^*,*, Hiroshi Asanuma, MD^*, Shoji Sanada, MD^*, Yulin Liao, MD^*, Seiji Takashima, MD^*, Masanori Asakura, MD^*, Hidezo Mori, MD, Yoshiro Shinozaki, MD, Masatsugu Hori, MD, FACC^* and Masafumi Kitakaze, MD, FACC

^* Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan
Department of Physiological Science, Tokai University School of Medicine, Isehara, Japan
Cardiovascular Division of Medicine, National Cardiovascular Center, Suita, Japan
Department of Cardiac Physiology, National Cardiovascular Center, Suita, Japan

Manuscript received April 30, 2001; revised manuscript received April 29, 2002, accepted May 24, 2002.

^* Reprint requests and correspondence: Dr. Koichi Node, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan.
node{at}medone.med.osaka-u.ac.jp

OBJECTIVES: We sought to investigate whether raloxifene reduces ischemia-reperfusion injury and what mechanisms are involved in the cardioprotective effects.

BACKGROUND: Estradiol-17-beta reduces myocardial infarct size in ischemia-reperfusion injury. Raloxifene, a selective estrogen receptor modulator, demonstrates immediate coronary artery vasorelaxing effects.

METHODS: The myocardial ischemia-reperfusion model included anesthetized open-chest dogs after 90-min occlusion of the left anterior descending coronary artery (LAD) and subsequent 6-h reperfusion. Raloxifene and/or other drugs were infused into the LAD from 10 min before coronary occlusion to 1 h after reperfusion without an occlusion period.

RESULTS: Infarct size was reduced in the raloxifene (5 µg/kg per min) group compared with the control group (7.2 ± 2.5% vs. 40.9 ± 3.9% of the area at risk, p < 0.01). Either N^G-nitro-L-arginine methyl ester (L-NAME), the inhibitor of nitric oxide (NO) synthase, or charybdotoxin, the blocker of Ca²⁺-activated K+ (K_Ca) channels, partially attenuated the infarct size–limiting effect, and both of them completely abolished the effect. The incidence of ventricular fibrillation was also less in the raloxifene group than in the control group (11% vs. 44%, p < 0.05). Activity of p38 mitogen-activated protein (MAP) kinase increased with 15-min ischemia, and raloxifene pretreatment inhibited the activity. Myeloperoxidase activity of the 6-h reperfused myocardium was also attenuated by raloxifene.

CONCLUSIONS: These data demonstrate that raloxifene reduces myocardial ischemia-reperfusion injury by mechanisms dependent on NO and the opening of K_Ca channels in canine hearts. Deactivation of p38 MAP kinase and myeloperoxidase by raloxifene may be involved in the cellular mechanisms of cardioprotection.

Abbreviations and Acronyms   CTX   charybdotoxin   ERK   extracellular signal–regulated protein kinase   JNK   c-Jun NH2-terminal protein kinase   KCa   Ca2+-activated K+   LAD   left anterior descending coronary artery   L-NAME   NG-nitro-L-arginine methyl ester   MAP   mitogen-activated protein   MBP   myelin basic protein   MI   myocardial infarct   MPO   myeloperoxidase   NO   nitric oxide

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