To study the effect of angiotensin II receptor AT1 blockade on blood pressure, gene
expression and pathomorphology of transgenic rats harbouring the mouse Ren-2 gene
[TGR(mREN2)27], that develop fulminant hypertension while exhibiting suppressed components
of the circulating renin-angiotensin system.
TGR(mREN2)27 were treated orally with the newly developed AT1-specific angiotensin
receptor antagonist Telmisartan, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)
methyl]-[1,1'-biphenyl]-2-carboxylic acid, in three doses (0.1, 1 and 3 mg/kg body
weight) for 9 weeks.
The concentrations of the renin-angiotensin system components were analysed in plasma
and tissues by radioimmunoassay. Messenger RNA levels for the angiotensinogen and
renin genes were quantified by RNAase protection assay in several tissues. Heart hypertrophy
and kidney morphology and function were monitored at the end of the treatment.
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 cardiovascular 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 unchanged in the hypothalamus, thymus and adrenal gland. In the
kidney, the expression of the endogenous, but not of the mouse Ren-2 gene, was increased
in parallel to the renin concentration. Telmisartan reduced the severe glomerulosclerosis
and proteinuria as well as cardiac hypertrophy 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 mmHg and the plasma renin-angiotensin system parameters were unchanged.
From these experiments using a specific antagonist we can conclude that high blood
pressure in TGR(mREN2)27 is angiotensin II-dependent. Furthermore, the expression
of the renin-angiotensin system genes seems to be regulated not only by blood pressure
and the plasma renin-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 influenced by angiotensin II
directly.