Olmesartan, a novel AT1 antagonist, suppresses cytotoxic myocardial injury in autoimmune heart failure.
Some ANG II receptor type 1 (AT(1)) antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. However, the effects of the drugs on autoimmune diseases are unknown. We tested the hypothesis that olmesartan, a novel AT(1) antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributed to the suppression of inflammatory cytokines as well as to the immunomodulatory action of the heart. We administered olmesartan orally at does of 1, 3, and 10 mg.kg(-1).day(-1) to rats with EAM for 3 wk. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group and markedly reduced the severity of myocarditis associated with the decrease of myocardial macrophage, CD4(+), and CD8(+) T-cell expression by comparison of heart wt-to-body wt ratios, pericardial effusion scores, and macroscopic and microscopic scores. Numbers of myocardial interleukin-1beta (IL-1beta)-positive-staining cells (obtained by immunohistochemistry) and quantities of IL-1beta expression (obtained by Western blotting) were significantly lower in rats with EAM given olmesartan treatment compared with rats given vehicle. Cardiac myosin-specific, delayed-type hypersensitivity was significantly lower in olmesartan-treated rats than in control rats. The cytotoxic activities of lymphocytes in rats with EAM treated with olmesartan were reduced compared with untreated control rats. In vitro study showed that both olmesartan and its active metabolite RNH-6270 suppressed IL-1beta production in U-937 cells and cultured myocytes. Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines as well as to suppressive effects of cytotoxic myocardial injury in addition to hemodynamic modifications.
Yuan
Zuyi
Z
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto Univ., 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Nimata
Masaomi
M
Okabe
Taka-Aki
TA
Shioji
Keisuke
K
Hasegawa
Koji
K
Kita
Toru
T
Kishimoto
Chiharu
C
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D009202:Cardiomyopathies / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D009205:Myocarditis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009218:Myosins; D000068557:Olmesartan Medoxomil; D009929:Organ Size; D051381:Rats; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D007375:Interleukin-1; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; D009218:Myosins