MOLECULAR EFFECTS OF M17055, FUROSEMIDE AND THIAZIDE ON CARDIAC-HYPERTROPHY OF SPONTANEOUSLY HYPERTENSIVE RATS

Although diuretics have been clinically shown to reduce cardiovascular morbidity and mortality, the effects of diuretics on cardiac hypertro phy are poorly understood. In this study, we examined the molecular ef fects of diuretics on hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHR) were given p.o. M17055 (a novel ''high ceiling '' diuretic) 1.25, 2.5 or 5 mg/kg/day, furosemide 50 mg/kg/day or tric hlormethiazide 30 mg/kg/day for 5 weeks. After the treatment, cardiac myosin isoforms were analyzed by gel electrophoresis, and cardiac hype rtrophy-related gene expressions were examined by Northern blot analys is. These three diuretics significantly reduced cardiac hypertrophy of SHR. M17055 and furosemide, but not trichlormethiazide, significantly increased the proportion of cardiac V3 myosin of SHR by enhancing the gene expression of beta-myosin heavy chain. On the other hand, trichl ormethiazide, but not M17055 or furosemide, suppressed the increased c ardiac gene expression of skeletal alpha-actin in SHR. Cardiac collage n type III expression of SHR was decreased only by treatment with M170 55. Plasma thyroid hormone levels of SHR were slightly decreased by M1 7055 and by furosemide and were negatively correlated with cardiac V3 myosin contents. Thus the effects on the gene expression of cardiac co ntractile proteins and collagen are significantly different among thes e three types of diuretics, which suggests that these diuretics may ha ve different cardiac actions independent of their diuretic and antihyp ertensive actions. The increased cardiac V3 myosin induced by M17055 a nd by furosemide may be partially due to the decreased plasma thyroid hormone.