ANGIOTENSIN-II TYPE-I RECEPTOR ANTAGONIST INHIBITS THE GENE-EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND EXTRACELLULAR-MATRIX IN CARDIAC AND VASCULAR TISSUES OF HYPERTENSIVE RATS

TCV-116 enyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate], a nonpeptid e selective angiotensin II type I receptor (ATI receptor) antagonist, at the dose of 0.1, 1 or In mg kg(-1) day(-1), was orally given to 22- week-old stroke-prone spontaneously hypertensive rats (SHRSP) for in w eeks (from the age of 22-32 weeks) to examine the effects on gene expr ession of transforming growth factor-beta 1 (TGF-beta 1) and extracell ular matrix proteins in the heart and blood vessels. Tissue messenger RNA (mRNA) was measured by northern blot analysis, with a specific com plementary DNA probe. In the heart, left ventricular mRNA levels for f ibronectin; types I, III and IV collagen; and laminin were significant ly higher in SHRSP than control Wistar-Kyoto rats. In the mesenteric a rtery and aorta of SHRSP, TGF-beta 1 mRNA and the mentioned extracellu lar matrix protein mRNAs were increased compared with Wistar-Kyoto rat s. Thus, the expression of various genes was up-regulated in cardiovas cular tissues of SHRSP. Treatment of SHRSP with TCV-116 suppressed the gene expression of the mentioned extracellular matrix proteins and TG F-beta 1 in both heart and blood vessels in a dose-dependent fashion. Furthermore, TCV-116 regressed cardiac hypertrophy and lessened the me dial hypertrophy of the aorta in SHRSP. These results show that angiot ensin AT1 receptor antagonist in vivo can inhibit the gene expression of TGF-beta 1 and extracellular matrix proteins in hypertensive cardio vascular tissues. These effects may contribute to the beneficial effec ts of AT1 receptor antagonist on hypertensive cardiac hypertrophy and vascular thickening.