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PRECLINICAL STUDY

Scavenging Free Radicals by Low-Dose Carvedilol Prevents Redox-Dependent Ca²⁺ Leak Via Stabilization of Ryanodine Receptor in Heart Failure

Mamoru Mochizuki, MD^_*,1, Masafumi Yano, MD, PhD^_*,1,_*, Tetsuro Oda, MD, PhD^_*, Hiroki Tateishi, MD^_*, Shigeki Kobayashi, MD, PhD^_*, Takeshi Yamamoto, MD, PhD^_*, Yasuhiro Ikeda, MD, PhD^_*, Tomoko Ohkusa, MD, PhD^_*, Noriaki Ikemoto, PhD^, and Masunori Matsuzaki, MD, PhD, FACC^_*

^_* Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Japan
Boston Biomedical Research Institute, Watertown, Massachusetts
Department of Neurology, Harvard Medical School, Boston, Massachusetts.

Manuscript received June 12, 2006; revised manuscript received December 11, 2006, accepted January 1, 2007.

^_* Reprint requests and correspondence: Dr. Masafumi Yano, Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan. (Email: yanoma{at}yamaguchi-u.ac.jp).

Objectives: We investigated whether defective intracellular Ca²⁺ handling is corrected by carvedilol in heart failure.

Background: In heart failure, the interaction between the N-terminal and central domains of the ryanodine receptor (RyR), the domains where many mutations have been found in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), is defective, as shown in our recent report.

Methods: Sarcoplasmic reticulum vesicles were isolated from canine left ventricular muscle (normal or 4-weeks rapid ventricular pacing). The RyR was labeled with the fluorescent conformational probe methylcoumarin acetate (MCA) with DPc10 (a synthetic peptide corresponding to Gly²⁴⁶⁰-Pro²⁴⁹⁵ of RyR, one of the mutable domains in CPVT) as a site-direction carrier.

Results: Normal cardiac function was well preserved in carvedilol-treated/paced dogs (CV+) but not in the untreated/paced dogs (CV–). In CV–, the interdomain interaction within RyR was defective (i.e., in an unzipped state), as determined by the fluorescence quenching technique. However, in CV+, the domain interaction remained normal (i.e., in a zipped state). In CV–, oxidative stress of RyR (reduction in the number of free thiols) was severe, but it was negligible in CV+. In (CV–) failing cardiomyocytes, incubation with low-dose CV (30 nmol/l), which eliminated intracellular reactive oxygen species with no acute effect on cell shortening, markedly improved the contractile function and Ca²⁺ transient. However, after domain unzipping by DPc10, CV was without effect.

Conclusions: Carvedilol, at a concentration that is sufficient to produce antioxidant effect, improves the intracellular Ca²⁺ handling and contractile dysfunction by correcting defective interdomain interaction within the RyR in the failing heart.

Abbreviations and Acronyms   CPVT = catecholaminergic polymorphic ventricular tachycardia   CV = carvedilol   DCFH-DA = 2',7'-dichlorofluorescin diacetate   DPc10 = a synthetic peptide corresponding to Gly2460-Pro2495 of ryanodine receptor   LV = left ventricle/ventricular   mBB = monobromobimane   MCA = methylcoumarin acetate   PKA = protein kinase A   PLB = phospholamban   ROS = reactive oxygen species   RV = rapid ventricular   RyR = ryanodine receptor   SIN-1 = 3-morpholinosydnonimine   SR = sarcoplasmic reticulum