Published Online
on August 14, 2006

A more recent version of this article appeared on August 29, 2006

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Submitted on December 14, 2005
Revised on May 26, 2006
Accepted on June 22, 2006

2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis. Potential Role of 2-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, and Tohru Izumi MD, PhD

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

^* To whom correspondence should be addressed. E-mail: mototsugu{at}smz.ja-shizuoka.or.jp.

Background--The therapeutic potential of 2-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 2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon- mRNA levels. Propranolol, a nonselective -AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a 1-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 2-selective AR agonists inhibited the activation of cardiac myosin fragment-specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a 2-selective AR antagonist. Furthermore, treatment with 2 different 2-selective AR agonists starting on day 14 also ameliorated EAM on day 21.

Conclusions--2-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. 2-AR-stimulating agents may represent important immunomodulators of the cardiac myosin-induced autoimmune process and have potential as a new therapy for myocarditis.

Key words: immune system • myocarditis • receptors, adrenergic, beta

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