Beta2-Adrenergic agonists suppress rat autoimmune myocarditis: potential role of beta2-adrenergic stimulants as new therapeutic agents for myocarditis.
BACKGROUND
The therapeutic potential of beta2-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.


RESULTS
Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the beta2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-gamma mRNA levels. Propranolol, a nonselective beta-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a beta1-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 beta2-selective AR agonists inhibited the activation of cardiac myosin fragment-specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a beta2-selective AR antagonist. Furthermore, treatment with 2 different beta2-selective AR agonists starting on day 14 also ameliorated EAM on day 21.


CONCLUSIONS
beta2-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. beta2-AR-stimulating agents may represent important immunomodulators of the cardiac myosin-induced autoimmune process and have potential as a new therapy for myocarditis.
Nishii
Mototsugu
M
Department of Internal Medicine and Cardiology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, 228-8555 Japan. mototsugu@smz.ja-shizuoka.or.jp
Inomata
Takayuki
T
Niwano
Hiroe
H
Takehana
Hitoshi
H
Takeuchi
Ichiro
I
Nakano
Hironari
H
Shinagawa
Hisahito
H
Naruke
Takashi
T
Koitabashi
Toshimi
T
Nakahata
Jun-ichi
J
Izumi
Tohru
T
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D017931:DNA Primers; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D000068759:Formoterol Fumarate; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D009205:Myocarditis / Q000276:immunology* / Q000517:prevention & control*; D011433:Propranolol / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000318:Adrenergic beta-Agonists; D017931:DNA Primers; D004983:Ethanolamines; D016753:Interleukin-10; D007371:Interferon-gamma; D011433:Propranolol; D000068759:Formoterol Fumarate