title: Angiotensin II receptor blockade in TGR(mREN2)27: effects of renin-angiotensin-system gene expression and cardiovascular functions.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Kreutz
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Schinke
authors.forename: B
authors.initials: B
authors.lastname: Djavidani
authors.forename: J
authors.initials: J
authors.lastname: Wagner
authors.forename: M
authors.initials: M
authors.lastname: Kaling
authors.forename: W
authors.initials: W
authors.lastname: Wienen
authors.forename: M
authors.initials: M
authors.lastname: Bader
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D030801:Animals, Genetically Modified / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure; D002319:Cardiovascular System / Q000503:physiopathology*; D015870:Gene Expression; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D051381:Rats; D012084:Renin-Angiotensin System / Q000235:genetics*; D013256:Steroids / Q000097:blood / Q000652:urine; D000077333:Telmisartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D013256:Steroids; D000077333:Telmisartan