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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.
AuthorsT Nakamura, T Kurashina, Y Saito, H Sumino, N Akuzawa, H Aizawa, H Sakamoto, Z Ono, R Nagai
JournalHypertension research : official journal of the Japanese Society of Hypertension (Hypertens Res) Vol. 21 Issue 4 Pg. 251-7 (Dec 1998) ISSN: 0916-9636 [Print] England
PMID9877518 (Publication Type: Journal Article)
Chemical References
  • Angiotensin-Converting Enzyme Inhibitors
  • Drug Combinations
  • Endothelin Receptor Antagonists
  • Enzyme Inhibitors
  • Imidazoles
  • Imidazolidines
  • Receptor, Endothelin A
  • Nitric Oxide
  • imidapril
  • NG-Nitroarginine Methyl Ester
Topics
  • Albuminuria (urine)
  • Angiotensin-Converting Enzyme Inhibitors (pharmacology)
  • Animals
  • Blood Pressure (drug effects)
  • Drug Combinations
  • Endothelin Receptor Antagonists
  • Enzyme Inhibitors (pharmacology)
  • Hypertension (prevention & control)
  • Hypertrophy, Left Ventricular (chemically induced, etiology, prevention & control)
  • Imidazoles (pharmacology)
  • Imidazolidines
  • Male
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nephrosclerosis (chemically induced, etiology, prevention & control)
  • Nitric Oxide (antagonists & inhibitors, biosynthesis)
  • Rats
  • Rats, Wistar
  • Receptor, Endothelin A
  • Time Factors

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