title: Angiotensin II type 1 receptor blockade prevents lethal malignant hypertension: relation to kidney inflammation.
abstract: BACKGROUND
  Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect.
  
  
  RESULTS
  Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg. kg(-1). d(-1) or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects.
  
  
  CONCLUSIONS
  Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.
authors.affiliation: Department of Medicine IV, University of Erlangen, Nürnberg, Germany. karl.hilgers@rzmail.uni-erlangen.de
authors.forename: K F
authors.initials: KF
authors.lastname: Hilgers
authors.forename: A
authors.initials: A
authors.lastname: Hartner
authors.forename: M
authors.initials: M
authors.lastname: Porst
authors.forename: R
authors.initials: R
authors.lastname: Veelken
authors.forename: J F
authors.initials: JF
authors.lastname: Mann
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006974:Hypertension, Malignant / Q000209:etiology / Q000517:prevention & control*; D006978:Hypertension, Renovascular / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009393:Nephritis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D015996:Survival Rate; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000068756:Valsartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine