title: ET(A) receptor antagonist ameliorates nephrosclerosis and left ventricular hypertrophy induced in rat by prolonged inhibition of nitric oxide synthesis.
abstract: We investigated the ability of the ETA receptor antagonist T-0115 and the angiotensin-converting enzyme (ACE) inhibitor imidapril hydrochloride to prevent hypertensive complications induced in rats by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/l, or L-NAME plus imidapril 10 mg/l in the drinking water. In rats treated with L-NAME 500 mg/l plus T-0115, T-0115 was given in the food at a dose of 0.2 mg/g food or 0.6 mg/g food. We then collected 24-h urine samples at 2, 4, and 6 wk, obtained blood samples at 6 wk, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90+/-0.65 vs. 0.05+/-0.02 mg/d/100 g in control), and the area of the left ventricular wall (83.3+/-3.0 vs. 69.8+/-1.8 mm2 in control). The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of T-0115 0.6 mg/g food with L-NAME ameliorated the tail-cuff pressure and the albuminuria (0.56+/-0.23 mg/d/100 g), although to a lesser extent than the changes seen with imidapril 10 mg/l. T-0115 0.6 mg/g food prevented left ventricular hypertrophy as effectively as imidapril 10 mg/l (70.8+/-1.8 with T-0115 vs. 68.3+/-2.7 mm2 with imidapril). Chronic inhibition of NO synthesis produced left ventricular hypertrophy and nephrosclerosis. Our results demonstrate that inhibition of the renin-angiotensin system morely effectively prevents nephrosclerosis than does the blockade of ETA receptors in a model of hypertension induced by chronic NO blockade. However, inhibition of the ET-1 pathway appeared to be as effective as ACE inhibitors in preventing left ventricular hypertrophy in this model.
authors.affiliation: Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Kurashina
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: H
authors.initials: H
authors.lastname: Sumino
authors.forename: N
authors.initials: N
authors.lastname: Akuzawa
authors.forename: H
authors.initials: H
authors.lastname: Aizawa
authors.forename: H
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Z
authors.initials: Z
authors.lastname: Ono
authors.forename: R
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000419:Albuminuria / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004338:Drug Combinations; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009400:Nephrosclerosis / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004338:Drug Combinations; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D044022:Receptor, Endothelin A; D009569:Nitric Oxide; C065166:imidapril; D019331:NG-Nitroarginine Methyl Ester