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TCV-116 [(+/-)-(cyclohexyloxycarbony-loxy)ethyl2-ethoxy-1-[[2' -(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate ], a nonpeptide selective angiotensin II type I receptor (AT1 receptor) antagonist, at the dose of 0.1, 1 or 10 mg kg-1 day-1, was orally given to 22-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 10 weeks (from the age of 22-32 weeks) to examine the effects on gene expression of transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix proteins in the heart and blood vessels. Tissue messenger RNA (mRNA) was measured by northern blot analysis, with a specific complementary DNA probe. In the heart, left ventricular mRNA levels for fibronectin; types I, III and IV collagen; and laminin were significantly higher in SHRSP than control Wistar-Kyoto rats. In the mesenteric artery and aorta of SHRSP, TGF-beta 1 mRNA and the mentioned extracellular matrix protein mRNAs were increased compared with Wistar-Kyoto rats. Thus, the expression of various genes was up-regulated in cardiovascular tissues of SHRSP. Treatment of SHRSP with TCV-116 suppressed the gene expression of the mentioned extracellular matrix proteins and TGF-beta 1 in both heart and blood vessels in a dose-dependent fashion. Furthermore, TCV-116 regressed cardiac hypertrophy and lessened the medial hypertrophy of the aorta in SHRSP. These results show that angiotensin AT1 receptor antagonist in vivo can inhibit the gene expression of TGF-beta 1 and extracellular matrix proteins in hypertensive cardiovascular tissues. These effects may contribute to the beneficial effects of AT1 receptor antagonist on hypertensive cardiac hypertrophy and vascular thickening. more...

The distribution of exogenously administered renin was investigated using whole body autoradiography. Purified renin from mouse submaxillary gland (SR) was labeled with radioactive iodine (125I). This labeled renin (125I-SR) and Na125I were administered into the tail vein of male ddY mice, in doses of 10.2 and 16.4 mu Ci/30 g body weight, respectively. Mice were killed by an overdose of ether, and autoradiography was performed on whole body sections. To separate free 125I liberated from 125I-SR, sections were treated with perchloric acid. A major accumulation of 125I-SR, acid-insoluble, was evident in the renal cortex, whereas the hepatic accumulation of 125I-SR was minor. Radioactivity in the thyroid and submaxillary glands, in the stomach, and in urine was also apparent, but disappeared after acid treatment, except in the thyroid glands. Radioactivity in the brain, intestinal content, spleen, and adrenal glands was nil. These autoradiograms provide the first evidence that exogenously administered renin is mainly distributed in the renal cortex. more...

We studied, by whole-body autoradiography, the distribution of exogenously administered renal renin in rat. Rat renal renin was completely purified and labeled with 125I ([125I]-renin) and was then injected into the tail veins of conscious rats at a dose of 30 microCi, 430 ng. After various intervals, rats were killed by an overdose of ether, the whole body rapidly frozen in acetone-dry ice, and autoradiography performed on sagittal whole-body sections. To remove breakdown products ([125I]-tyrosine and free 125I) from [125I]-renin, sections were treated with perchloric acid solution. The main accumulation of [125I]-renin acid-insoluble radioactivity was observed in liver and renal cortex. The accumulation in these organs was already evident 2 min after the injection, reached a maximum level by 15 min, then gradually decreased. A small amount of [125I]-renin was also evident in spleen, bone marrow, and adrenal gland. Thirty min after the injection, radioactivity began to appear in the thyroid gland, stomach, and small intestine, but disappeared with acid treatment, except in the thyroid. Radioactivity was negligible in other organs including brain, submaxillary gland, lung, heart, and testis. These autoradiographs clearly demonstrate that exogenously administered renal renin is distributed mainly in the liver and renal cortex. more...

Although diuretics have been clinically shown to reduce cardiovascular morbidity and mortality, the effects of diuretics on cardiac hypertrophy are poorly understood. In this study, we examined the molecular effects 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 trichlormethiazide 30 mg/kg/day for 5 weeks. After the treatment, cardiac myosin isoforms were analyzed by gel electrophoresis, and cardiac hypertrophy-related gene expressions were examined by Northern blot analysis. 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, trichlormethiazide, but not M17055 or furosemide, suppressed the increased cardiac gene expression of skeletal alpha-actin in SHR. Cardiac collagen type III expression of SHR was decreased only by treatment with M17055. Plasma thyroid hormone levels of SHR were slightly decreased by M17055 and by furosemide and were negatively correlated with cardiac V3 myosin contents. Thus the effects on the gene expression of cardiac contractile proteins and collagen are significantly different among these three types of diuretics, which suggests that these diuretics may have different cardiac actions independent of their diuretic and antihypertensive actions. The increased cardiac V3 myosin induced by M17055 and by furosemide may be partially due to the decreased plasma thyroid hormone. more...