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(Circulation. 2006;114:936-944.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

ß2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis

Potential Role of ß2-Adrenergic Stimulants as New Therapeutic Agents for Myocarditis

Mototsugu Nishii, PhD, MD; Takayuki Inomata, MD, PhD; Hiroe Niwano, MD, PhD; Hitoshi Takehana, MD, PhD; Ichiro Takeuchi, MD, PhD; Hironari Nakano, MD, PhD; Hisahito Shinagawa, MD; Takashi Naruke, MD; Toshimi Koitabashi, MD, PhD; Jun-ichi Nakahata, MD; Tohru Izumi, MD, PhD

From the Department of Internal Medicine and Cardiology, Kitasato University School of Medicine, Sagamihara, Japan.

Correspondence to Dr Mototsugu Nishii, Department of Internal Medicine and Cardiology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, 228-8555 Japan. E-mail mototsugu{at}smz.ja-shizuoka.or.jp

Received December 14, 2005; revision received May 26, 2006; accepted June 22, 2006.

Background— The therapeutic potential of ß2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure–induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated.

Methods and Results— Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the ß2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon- mRNA levels. Propranolol, a nonselective ß-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a ß1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin–primed lymph node cells from drug-treated rats. In vitro addition of ß2-selective AR agonists inhibited the activation of cardiac myosin fragment–specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a ß2-selective AR antagonist. Furthermore, treatment with 2 different ß2-selective AR agonists starting on day 14 also ameliorated EAM on day 21.

Conclusions— ß2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin–specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. ß2-AR–stimulating agents may represent important immunomodulators of the cardiac myosin–induced autoimmune process and have potential as a new therapy for myocarditis.

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