temocapril-hydrochloride and Cardiomyopathies

Because hepatocyte growth factor (HGF) prevented and/or regressed fibrosis in liver and pulmonary injury models, HGF may play an important role in the pathogenesis of fibrotic cardiovascular disease. Because angiotensin (Ang) II significantly decreased local HGF production, we performed (1) in vitro experiments using fibroblasts and (2) administration of an ACE inhibitor (temocapril) and an Ang II type 1 receptor antagonist (CS-866) to cardiomyopathic hamsters.. In human fibroblasts, HGF significantly increased the production of matrix metalloprotease-1 (MMP-1) and urokinase plasminogen activator, whereas HGF also significantly attenuated the reduction of MMP-1 activity induced by Ang II. In contrast, HGF significantly decreased transforming growth factor (TGF)-beta mRNA stimulated by Ang II, whereas HGF also decreased basal TGF-beta protein level without affecting growth. Similarly, in rat cardiac fibroblasts, HGF inhibited the expression and production of TGF-beta, whereas HGF upregulated its specific receptor, c-met. Conversely, in vivo experiments revealed that administration of temocapril and CS-866 to cardiomyopathic hamsters resulted in a significant decrease in fibrotic area and increase in cardiac HGF concentration and mRNA (P<0.01), whereas cardiac concentration and mRNA of HGF were significantly decreased in cardiomyopathic hamsters. In contrast, mRNA expression of collagen III was markedly decreased by treatment with temocapril and CS-866.. Here, we demonstrated that Ang II blockade prevented myocardial fibrosis in the cardiomyopathic hamster, accompanied by a significant increase in cardiac HGF. Overall, increase in local HGF expression may participate in the prevention of myocardial injury by Ang II blockade through its antifibrotic action.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathies; Cells, Cultured; Collagen; Cricetinae; Extracellular Matrix; Fibroblasts; Fibrosis; Hepatocyte Growth Factor; Humans; Imidazoles; In Vitro Techniques; Male; Matrix Metalloproteinase 1; Muscle Fibers, Skeletal; Myocardium; Olmesartan Medoxomil; Rats; Tetrazoles; Thiazepines; Ventricular Remodeling

The purpose of our study has to determine the myocardial protective effects of the angiotensin-converting enzyme (ACE) inhibitor temocapril (TEM, 7 mg/kg/day) simultaneously administered with doxorubicin (Adriamycin). Twenty male Sprague-Dawley rats were intraperitoneally administered a cumulative dose of 15 mg/kg of doxorubicin (each dose of 1.0 mg/kg x 15) for 3 weeks, and divided into TEM-untreated and -treated rats. Seven control rats were injected with saline intraperitoneally. Body weight, hemodynamics, and echocardiographic measurements including quantitative analysis of ultrasonic integrated backscatter (IB) were obtained for 12 weeks after treatment. Finally, rats were killed for histopathologic study. At 6 weeks, end-diastolic left ventricular diameter (LVD) and percentage fractional shortening (%FS) were similar in TEM-treated and TEM-untreated rats, but cyclic variation of IB (dB) significantly decreased in TEM-untreated rats (7.3 +/- 1.2; control rats, 9.7 +/- 0.9; p < 0.01). At 12 weeks, %FS decreased in TEM-untreated rats (26.1 +/- 6.1%: TEM-treated rats, 34.2 +/- 6.2; p < 0.05), and calibrated IB (dB) in TEM-untreated rats (15.5 +/- 0.5) increased as compared with that in TEM-treated rats (12.1 +/- 0.7; p < 0.01). Interstitial collagen accumulation increased in TEM-untreated rats and was inhibited in treated rats. Simultaneous administration of TEM with doxorubicin was beneficial in preventing doxorubicin-induced myocardial damage, and myocardial tissue characterization was useful for the early detection of myocardial damage and the assessment of therapy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Pressure; Body Weight; Cardiomyopathies; Collagen; Densitometry; Doxorubicin; Echocardiography; Male; Rats; Rats, Sprague-Dawley; Thiazepines