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Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall.

Abstract
Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and systemic inflammation, with subsequent brain and renal disorders and early death. We tested the hypothesis that valsartan, an angiotensin II type 1 (AT1) receptor antagonist, exerts protective effects in SHRSP through its anti-inflammatory properties, even in the absence of a blood pressure-lowering effect. SHRSP fed a high-salt diet were treated with vehicle or valsartan (1-10 mg/kg/day). The vehicle-treated rats developed hypertension, proteinuria, progressive kidney disease, and, 40 +/- 5 days from the beginning of the treatment, brain damage as visualized by magnetic resonance imaging. Rats treated with 1 mg/kg/day valsartan developed brain damage after 61 +/- 3 days (p <0.01 versus vehicle-treated rats). No damage showed after 100 days in 80% of the rats treated with 10 mg/kg/day. Valsartan treatment preserved renal structure, by preventing the infiltration of inflammatory cells, and lowered renal expression of monocyte chemoattractant protein-1, transforming growth factor-beta1, and interleukin-1beta, compared with vehicle-treated SHRSP. Urinary excretion of acute-phase proteins increased in the latter but remained negligible in the drug-treated animals. Furthermore, valsartan exerted protective effects also when given after established proteinuria. In SHRSP, blockade of AT1 receptor with valsartan prevents the development of proteinuria, delays the appearance of brain damage, preserves renal structure, and increases survival under stressful conditions. Valsartan exerts its beneficial effects independently of any blood pressure fall and by means of broad anti-inflammatory actions both at local and at systemic levels. These observations indicate that the administration of AT1 receptor antagonists may be useful in pathological situations in which an anti-inflammatory effect is required.
AuthorsLuigi Sironi, Paolo Gelosa, Uliano Guerrini, Cristina Banfi, Veronica Crippa, Maura Brioschi, Elisabetta Gianazza, Elena Nobili, Anita Gianella, Marc de Gasparo, Elena Tremoli
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 3 Pg. 989-95 (Dec 2004) ISSN: 0022-3565 [Print] United States
PMID15302895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiotensin II Type 1 Receptor Blockers
  • Anti-Inflammatory Agents
  • Ccl2 protein, rat
  • Chemokine CCL2
  • Interleukin-1
  • RNA, Messenger
  • Tetrazoles
  • Transforming Growth Factor beta
  • Valsartan
  • Valine
Topics
  • Angiotensin II Type 1 Receptor Blockers (therapeutic use)
  • Animals
  • Anti-Inflammatory Agents
  • Blood Pressure (drug effects, physiology)
  • Body Weight (drug effects)
  • Brain (pathology)
  • Chemokine CCL2 (biosynthesis)
  • Immunohistochemistry
  • Interleukin-1 (biosynthesis)
  • Kidney (pathology)
  • Magnetic Resonance Imaging
  • Male
  • Proteinuria (chemically induced)
  • RNA, Messenger (biosynthesis)
  • Rats
  • Rats, Inbred SHR
  • Stroke (drug therapy, genetics, pathology)
  • Survival Analysis
  • Tetrazoles (therapeutic use)
  • Transforming Growth Factor beta (biosynthesis)
  • Valine (analogs & derivatives, therapeutic use)
  • Valsartan

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