eprosartan and Body-Weight

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.

Topics: Acrylates; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Blotting, Western; Body Weight; Dietary Fats; Disease Progression; Extracellular Matrix; Fibrinolysin; Gene Expression Regulation; Heart Rate; Hypertension; Imidazoles; Kidney Diseases; Male; Organ Size; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Serine Proteinase Inhibitors; Sodium Chloride, Dietary; Stroke; Thiophenes; Thrombosis

Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP).. SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups.. Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05).. These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Topics: Acrylates; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Heart Rate; Hypertension; Imidazoles; Kidney; Magnetic Resonance Imaging; Male; Myocardium; Natriuresis; Organ Size; Peptide Fragments; Protein Precursors; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Survival Rate; Thiophenes; Ventricular Remodeling

All components of the renin-angiotensin system have been demonstrated in the brain and AT1 receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT1 receptor antagonists, which are increasingly used in the treatment of arterial hypertension and chronic heart failure, have the potential to mediate action via the central renin-angiotensin system. Therefore, we tested the in vivo access of the non-peptide AT1 receptor antagonist, eprosartan (30 and 60 mg per kg of body weight (BW) for 4 weeks, i.p. administered by osmotic minipumps), to angiotensin II receptors in the rat brain by in vitro autoradiography with 125I- (Sar1- Ile8) angiotensin II as a ligand. Eprosartan significantly increased plasma renin activity by four-fold and six-fold at doses of 30 and 60 mg x kg(-1), respectively (P< 0.05 vs CTRL). In the brain, eprosartan produced a dose-dependent inhibition of AT receptor binding in the median cerebral artery ( 850 +/- 249 and 650 +/- 106 vs 1072 +/- 116 dpm x mm(-2) of CTRL; P< 0.05). Furthermore, eprosartan inhibited angiotensin II receptor binding in discrete brain areas, which express exclusively, or predominantly, AT1 receptors both outside and within the blood-brain barrier, such as the paraventricular nucleus ( 180 +/- 47 and 130 +/- 18 vs 545 +/- 99 dpm x mm(-2)of CTRL; P< 0.05), the subfornical organ ( 106 +/- 26 and 112 +/- 17 vs 619 +/- 256 dpm x mm(-2)of CTRL; P< 0.05), and the organum vasculosum laminae terminalis ( 461 +/- 110 and 763 +/- 136 vs 1033 +/- 123 dpmx mm(-2)of CTRL; P< 0.05). These results emphasize that eprosartan readily crosses the blood-brain barrier in vivo and selectively inhibits binding to AT1 receptors in specific brain nuclei. The modulation of central regulatory mechanisms might contribute to AT1 receptor antagonists overall therapeutic efficacy in cardiovascular disease.

Topics: Acrylates; Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Autoradiography; Blood Pressure; Blood-Brain Barrier; Body Weight; Brain; Heart Rate; Imidazoles; Male; Radiography; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin; Thiophenes