The Angiotensin Type 1 Receptor Antagonist, Eprosartan, Attenuates the Progression of Renal Disease in Spontaneously Hypertensive Stroke-Prone Rats with Accelerated Hypertension

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 301; no. 1; pp. 21 - 28
• Main Authors: Abrahamsen, Christian T, Barone, Frank C, Campbell, Jr, Wallace G, Nelson, Allen H, Contino, Lisa C, Pullen, Mark A, Grygielko, Eugene T, Edwards, Richard M, Laping, Nicholas J, Brooks, David P
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.04.2002
• Subjects: Acrylates - therapeutic use; Angiotensin Receptor Antagonists; Animals; Blood Pressure - drug effects; Blotting, Western; Body Weight - physiology; Dietary Fats; Disease Progression; Extracellular Matrix - pathology; Fibrinolysin - physiology; Gene Expression Regulation - drug effects; Heart Rate - drug effects; Hypertension - complications; Hypertension - genetics; Hypertension - pathology; Imidazoles - therapeutic use; Kidney Diseases - etiology; Kidney Diseases - pathology; Kidney Diseases - prevention & control; Male; Organ Size - physiology; Plasminogen Activator Inhibitor 1 - pharmacology; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin - genetics; Serine Proteinase Inhibitors - pharmacology; Sodium Chloride, Dietary; Stroke - pathology; Thiophenes; Thrombosis - pathology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.301.1.21

The effects of the angiotensin type 1 (AT 1 ) receptor antagonist, eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 ± 9 versus 284 ± 8 mm Hg), renal expression of transforming growth factor-β mRNA (1.5 ± 0.2 versus 5.4 ± 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 ± 1.4 versus 31.4 ± 10.7), fibronectin (2.2 ± 0.6 versus 8.2 ± 2.2), collagen I-α1 (5.6 ± 2.0 versus 23.8 ± 7.3), and collagen III (2.7 ± 0.9 versus 7.6 ± 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [=1.0]. Expression of fibronectin protein was also lowered by eprosartan (0.8 ± 0.1 versus 1.9 ± 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 ± 2 versus 127 ± 13 mg/day) and histological evidence of active renal damage (5 ± 2 versus 195 ± 6) and renal fibrosis (5.9 ± 0.7 versus 16.4 ± 1.9) in vehicle- versus eprosartan-treated rats, respectively. Our results demonstrated that AT 1 receptor blockade with eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-β1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.