Search

Favorable effects of angiotensin II type 1 receptor blockers on patients with ischemic or idiopathic dilated cardiomyopathy (DCM) have already been suggested by several human trials, but their effects on DCM remain unknown. Hence, we investigated the effect of olmesartan on myocardial remodeling in a rat model in which myosin-induced experimental autoimmune myocarditis (EAM) might develop into DCM. EAM was elicited in Lewis rats by immunization with cardiac myosin, and 28 d after immunization, the surviving Lewis rats were divided into two groups and treated with either olmesartan (10 mg/kg/d) or vehicle. Age-matched normal rats without immunizations were also used. After four weeks of treatment, we investigated the effects of olmesartan on cardiac function, inflammatory cytokines and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Olmesartan significantly reduced cardiac fibrosis as well as hypertrophy and its molecular markers (left ventricular [LV] mRNA expressions of transforming growth factor beta1, collagen-I and -III, and atrial natriuretic peptide) compared with those of vehicle-treated rats. Increased myocardial mRNA expressions of proinflammatory cytokines (interleukin [IL]-6, IL-1β), monocyte chemoattractant protein-1 and matrix metalloproteinases (MMP-2 and -9) were also suppressed by the treatment with olmesartan in rats with DCM. Further, the plasma level of angiotensin II was significantly increased in olmesartan-treated rats. These findings demonstrate that olmesartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with DCM after EAM.

Chymase has been known as a local angiotensin II–generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-β1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-β1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.