Angiotensin II subtype-1 receptor antagonists improve hemodynamic and renal changes without affecting glucose metabolisms in genetic rat model of non–insulin-dependent diabetes mellitus

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non–insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-1 receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat....

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Bibliographic Details
Published in:American journal of hypertension 1999, Vol.12 (1), p.21-27
Main Authors: Uehara, Yoshio, Hirawa, Nobuhito, Kawabata, Yukari, Numabe, Atsushi, Gomi, Tomoko, Ikeda, Toshio, Omata, Masao
Format: Article
Language:English
Subjects:
Acetylglucosaminidase - urine
Angiotensin
angiotensin receptor antagonist
Angiotensin Receptor Antagonists
Animals
Arterial hypertension. Arterial hypotension
Biological and medical sciences
Blood and lymphatic vessels
Blood Glucose - metabolism
Blood Pressure - drug effects
Cardiology. Vascular system
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - physiopathology
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - physiopathology
Diabetic Nephropathies - drug therapy
Diabetic Nephropathies - metabolism
Diabetic Nephropathies - physiopathology
Experimental diseases
hypertension
Imidazoles - therapeutic use
insulin
Kidney Glomerulus - drug effects
Kidney Glomerulus - metabolism
Kidney Glomerulus - pathology
Medical sciences
non–insulin-dependent diabetes mellitus
Organ Size
Pyridines - therapeutic use
Rats
Rats, Long-Evans
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
renal injury
Tetrazoles - therapeutic use
Treatment Outcome
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Summary:The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non–insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-1 receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat. OLETF rats fed a regular chow were treated with ANGII subtype-1 receptor antagonists (E4177 or TA606) for 22 weeks. Hemodynamic changes, glucose metabolism, and the effects on diabetic nephropathy were examined. Systolic blood pressure increased in OLETF rats in an age-dependent manner. OLETF rats exhibited increases in plasma concentrations of glucose and insulin and developed glucosuria at the age of 28 weeks. The changes in glucose metabolism were associated with proteinuria and an increase in urinary excretion of N-acetyl-β- D-glucosaminidase (NAG). Morphologic investigation revealed nodular lesions in glomeruli in the OLETF rats. The ANGII receptor antagonist treatment abolished the blood pressure elevation. However, the treatment did not affect plasma glucose and insulin levels and did not significantly reduce glucosuria. Nodular lesions in glomeruli were not improved by the treatment. However, the receptor antagonists significantly reduced proteinuria and urinary NAG excretion. Multivariate analyses revealed that proteinuria was determined by systolic blood pressure, lipid metabolism, and glucose levels in plasma. ANGII subtype-1 antagonism does not improve glucose metabolism in the OLETF rat model of NIDDM, which has abnormalities in the glucose-uptake system. Blood pressure elevation and part of the proteinuria associated with NIDDM depends on the renin-angiotensin system rather than glucose metabolisms per se.
ISSN:0895-7061
1879-1905
DOI:10.1016/S0895-7061(98)00276-3