QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.072066v1 311/3/989    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sironi, L. Articles by Tremoli, E. Search for Related Content PubMed PubMed Citation Articles by Sironi, L. Articles by Tremoli, E.

CARDIOVASCULAR

Anti-Inflammatory Effects of AT1 Receptor Blockade Provide End-Organ Protection in Stroke-Prone Rats Independently from Blood Pressure Fall

Department of Pharmacological Sciences (L.S., P.G., U.G., C.B., V.C., M.B., E.G., E.N., A.G., E.T.), Centre for Excellence on Neurodegenerative Diseases (L.S., E.G., E.T.), Proteomic and Protein Structure Study Group (E.G.), University of Milan, Milan, Italy; MG Consulting Company (M.d.G.), Rossemaison, Switzerland; and Monzino Cardiologic Centre IRCCS (C.F., M.B., E.T.), Milan, Italy

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-1, and interleukin-1, 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.

Address correspondence to: Luigi Sironi, Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, via Balzaretti 9, I-20133 Milano, Italy. E-mail: luigi.sironi{at}unimi.it

This article has been cited by other articles:

				G. T. Cicila, E. E. Morgan, S. J. Lee, P. Farms, S. Yerga-Woolwine, E. J. Toland, R. S. Ramdath, K. Gopalakrishnan, K. Bohman, A. L. Nestor-Kalinoski, et al. Epistatic Genetic Determinants of Blood Pressure and Mortality in a Salt-Sensitive Hypertension Model Hypertension, April 1, 2009; 53(4): 725 - 732. [Abstract] [Full Text] [PDF]

				Y. Ochiai, Y.-Q. Liang, M. Serizawa, and N. Kato Dynamic changes of the renin-angiotensin and associated systems in the rat after pharmacological and dietary interventions in vivo Physiol Genomics, November 12, 2008; 35(3): 330 - 340. [Abstract] [Full Text] [PDF]

				J. Li, Y. Doerffel, B. Hocher, and T. Unger Inflammation in the genesis of hypertension and its complications the role of angiotensin II Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3107 - 3109. [Full Text] [PDF]

				M. L. Graciano, C. R. Mouton, M. E. Patterson, D. M. Seth, J. J. Mullins, and K. D. Mitchell Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension Am J Physiol Renal Physiol, June 1, 2007; 292(6): F1858 - F1866. [Abstract] [Full Text] [PDF]

				B. Rodriguez-Iturbe and R. J. Johnson Role of inflammatory cells in the kidney in the induction and maintenance of hypertension Nephrol. Dial. Transplant., February 1, 2006; 21(2): 260 - 263. [Full Text] [PDF]

				B. Rodriguez-Iturbe, A. Ferrebuz, V. Vanegas, Y. Quiroz, S. Mezzano, and N. D. Vaziri Early and Sustained Inhibition of Nuclear Factor-{kappa}B Prevents Hypertension in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 51 - 57. [Abstract] [Full Text] [PDF]