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(Circulation. 2004;109:911-919.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure

Shinichi Okuda, MD^*; Masafumi Yano, MD, PhD^*; Masahiro Doi, MD, PhD; Tetsuro Oda, MD; Takahiro Tokuhisa, MD; Masateru Kohno, MD; Shigeki Kobayashi, MD, PhD; Takeshi Yamamoto, MD, PhD; Tomoko Ohkusa, MD, PhD; Masunori Matsuzaki, MD, PhD

From the Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan.

Correspondence to Masafumi Yano, MD, PhD, Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan. E-mail yanoma{at}po.cc.yamaguchi-u.ac.jp

Received March 18, 2003; de novo received August 8, 2003; revision received October 13, 2003; accepted October 14, 2003.

Background— Although angiotensin II receptor blockade is considered to be useful for the treatment of human heart failure, little beneficial hemodynamic effect has been shown in some experimental failing hearts. In this study, we assessed the effect of an angiotensin II receptor blocker, valsartan, on sarcoplasmic reticulum (SR) function, defectiveness of which is a major pathogenic mechanism in heart failure.

Methods and Results— SR vesicles were isolated from dog left ventricular muscle (normal or exposed to 4-week rapid ventricular pacing with or without valsartan). In the untreated and valsartan-treated paced dogs, cardiac function showed similar deterioration (compared with before pacing). However, both the density of ß-receptors and the contractile response to dobutamine were greater in the valsartan-treated paced dogs than in the untreated paced dogs. In untreated paced hearts, the ryanodine receptor was protein kinase A–hyperphosphorylated, showed an abnormal Ca²⁺ leak, and had a decreased amount of ryanodine receptor–bound FKBP12.6. No such phenomena were seen in the valsartan-treated paced hearts. Both the SR Ca²⁺ uptake function and the amount of Ca²⁺-ATPase were decreased in the untreated failing SR, but both were restored in the valsartan-treated SR.

Conclusions— During the development of pacing-induced heart failure, valsartan preserved the density of ß-receptors and concurrently restored SR function without improving resting cardiac function.

Key Words: sarcoplasmic reticulum • heart failure • calcium • ion channels

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