ANGIOTENSIN-II RECEPTOR BLOCKADE IN TCR(MREN2)27 - EFFECTS OF RENIN-ANGIOTENSIN-SYSTEM GENE-EXPRESSION AND CARDIOVASCULAR FUNCTIONS

Objective: To study the effect of angiotensin II receptor AT(1) blocka de on blood pressure, gene expression and pathomorphology of transgeni c rats harbouring the mouse Ren-2 gene [TGR(mREN2)27], that develop fu lminant hypertension while exhibiting suppressed components of the cir culating renin-angiotensin system. Design: TGR(mREN2)27 were treated o rally with the newly developed AT(1)-specific angiotensin receptor ant agonist Telmisartan, dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl ) methyl]-[1,1'-biphenyl]-2-carboxylic acid, in three doses (0.1, 1 an d 3 mg/kg body weight) for 9 weeks. Methods: The concentrations of the renin-angiotensin system components were analysed in plasma and tissu es by radioimmunoassay. Messenger RNA levels for the angiotensinogen a nd renin genes were quantified by RNAase protection assay in several t issues. Heart hypertrophy and kidney morphology and function were moni tored at the end of the treatment. Results: In contrast to 0.1 mg/kg, 1 and 3 mg/kg Telmisartan normalized tail blood pressure measured once a week. Plasma renin and angiotensin II concentration increases were dose-dependent. The renin-angiotensin system genes in various cardiova scular organs were differentially regulated by angiotensin II receptor blockade. Treatment with Telmisartan stimulated angiotensinogen gene expression in the liver, kidney and heart, whereas it remained unchang ed in the hypothalamus, thymus and adrenal gland. In the kidney, the e xpression of the endogenous, but not of the mouse Ren-2 gene, was incr eased in parallel to the renin concentration. Telmisartan reduced the severe glomerulosclerosis and proteinuria as well as cardiac hypertrop hy observed in untreated TGR(mREN2)27 even with the lowest dose of 0.1 mg/kg, at which the blood pressure of the rats still exceeded 225 mmH g and the plasma renin-angiotensin system parameters were unchanged. C onclusion: From these experiments using a specific antagonist we can c onclude that high blood pressure in TGR(mREN2)27 is angiotensin II-dep endent. Furthermore, the expression of the renin-angiotensin system ge nes seems to be regulated not only by blood pressure and the plasma re nin-angiotensin system but also by other, tissue-specific mechanisms. Pathomorphological changes in the kidney and in the heart do not seem to be caused by the systemic hypertension exclusively, but are also in fluenced by angiotensin II directly.