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(Circulation. 2000;102:458.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Cardioprotective Mechanism of Ischemic Preconditioning Is Impaired by Postinfarct Ventricular Remodeling Through Angiotensin II Type 1 Receptor Activation

Takayuki Miki, MD, PhD; Tetsuji Miura, MD, PhD; Akihito Tsuchida, MD, PhD; Atsushi Nakano, MD; Tohru Hasegawa, MD; Takayuki Fukuma, MD; Kazuaki Shimamoto, MD, PhD

From the Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Correspondence to Tetsuji Miura, MD, PhD, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail miura{at}sapmed.ac.jp

Background—Activation of protein kinase C–linked receptors and subsequent opening of the mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel are crucial in preconditioning (PC). This study examined whether postinfarct ventricular remodeling interferes with the PC mechanism.

Methods and Results—Two weeks before isolation of hearts, rabbits underwent a sham operation or coronary ligation (COL) to induce remodeling. Isolated buffer-perfused hearts were subjected to 30-minute global ischemia/2-hour reperfusion, and infarct size was expressed as a percentage of the left ventricle (%I/LV), from which the scarred infarct by COL was excluded. Although %I/LV was similar in sham-operated and remodeled hearts (52.9±6.5% versus 45.8±5.2%), PC with 2 episodes of 5-minute ischemia protected sham-operated but not remodeled hearts (%I/LV=18.1±2.5% versus 54.8±2.9%, P<0.05). Infusion of valsartan (10 mg · kg^-1 · d^-1), an angiotensin II type 1 (AT₁) receptor blocker, for 2 weeks after COL prevented the ventricular remodeling and preserved the response to PC (%I/LV=27.4±3.8%), although valsartan alone did not change %I/LV. Diazoxide, a mitoK_ATP channel opener, protected both sham-operated and remodeled hearts (%I/LV=14.1±3.1% and 8.3±3.6%).

Conclusions—The myocardium remodeled after infarction is refractory to PC, which is probably due to interruption of cellular signaling by PC upstream of mitoK_ATP channels. An AT₁ receptor blocker is beneficial not only for suppression of ventricular remodeling but also for preservation of the PC mechanism.

Key Words: preconditioning • myocardial infarction • remodeling • angiotensin • receptors • ion channels

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