The angiotensin type 1 receptor antagonist, eprosartan, attenuates the progression of renal disease in spontaneously hypertensive stroke-prone rats with accelerated hypertension.
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-beta 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-alpha 1 (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-beta1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.
Abrahamsen
Christian T
CT
Department of Renal Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406-0939, USA.
Barone
Frank C
FC
Campbell
Wallace G
WG
Nelson
Allen H
AH
Contino
Lisa C
LC
Pullen
Mark A
MA
Grygielko
Eugene T
ET
Edwards
Richard M
RM
Laping
Nicholas J
NJ
Brooks
David P
DP
D000179:Acrylates / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats; D018450:Disease Progression; D005109:Extracellular Matrix / Q000473:pathology; D005341:Fibrinolysin / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000473:pathology*; D007093:Imidazoles / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D009929:Organ Size / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D017673:Sodium Chloride, Dietary; D020521:Stroke / Q000473:pathology*; D013876:Thiophenes; D013927:Thrombosis / Q000473:pathology
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D004041:Dietary Fats; D007093:Imidazoles; D017395:Plasminogen Activator Inhibitor 1; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D015842:Serine Proteinase Inhibitors; D017673:Sodium Chloride, Dietary; D013876:Thiophenes; C068373:eprosartan; D005341:Fibrinolysin