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Angiotensin blockade improves cardiac and renal complications of type II diabetic rats
S Kim1, H Wanibuchi, A Hamaguchi
1Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
Abstract:
Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new model of human non-insulin-dependent diabetes mellitus (NIDDM), we examined the role of local angiotensin II in cardiovascular and renal complications of NIDDM. OLETF rats were orally given cilazapril (an angiotensin-converting enzyme inhibitor, 1 or 10 mg/kg), E4177 (an angiotensin AT1 receptor antagonist, 10 mg/kg), or vehicle for 26 or 40 weeks (from the age of 20 to 46 or 60 weeks). Cardiac mRNAs were measured by Northern blot analysis, and the thickening of the coronary arterial wall and the degree of perivascular fibrosis were determined by an image analyzer. Cilazapril or E4177 did not significantly affect body weight or plasma glucose and insulin levels of OLETF rats, indicating the minor effects on diabetes itself. However, both drugs significantly and similarly prevented coronary microvascular remodeling (the increase in wall thickening and perivascular fibrosis in coronary arterioles and small coronary arteries) in OLETF rats, and they were associated with the suppression of cardiac transforming growth factor-beta1 expression. Both drugs suppressed not only the increase in left ventricular weight but also the downregulation of cardiac alpha-myosin heavy chain expression in OLETF rats. Glomerulosclerosis and glomerular hypertrophy in OLETF rats were improved by cilazapril and E4177 to a comparable extent. These results, taken together with the fact that OLETF rats show normal plasma renin levels, support that the AT1 receptor is involved in the pathogenesis of cardiac and renal complications in NIDDM.
Insights
Angiotensin II AT1 receptor blockade prevents cardiovascular and renal complications in a non-insulin-dependent diabetes mellitus (NIDDM) rat model. These findings highlight the AT1 receptor
Area of Science:
- Cardiovascular Research
- Nephrology
- Endocrinology
Background:
- Non-insulin-dependent diabetes mellitus (NIDDM) is associated with significant cardiovascular and renal complications.
- The role of local angiotensin II in NIDDM-related organ damage requires further elucidation.
- Otsuka Long-Evans Tokushima Fatty (OLETF) rats serve as a valuable model for studying human NIDDM.
Purpose of the Study:
- To investigate the involvement of local angiotensin II in the cardiovascular and renal complications of NIDDM.
- To evaluate the therapeutic effects of an angiotensin-converting enzyme inhibitor (cilazapril) and an angiotensin AT1 receptor antagonist (E4177) in NIDDM rats.
Main Methods:
- OLETF rats were treated with cilazapril, E4177, or vehicle for 26 or 40 weeks.
- Cardiac mRNA expression was analyzed using Northern blot.
- Coronary microvascular remodeling, left ventricular weight, and renal changes (glomerulosclerosis, glomerular hypertrophy) were assessed.
Main Results:
- Cilazapril and E4177 did not significantly alter body weight, plasma glucose, or insulin levels in OLETF rats.
- Both drugs effectively prevented coronary microvascular remodeling and suppressed cardiac transforming growth factor-beta1 expression.
- Treatment with cilazapril or E4177 mitigated left ventricular hypertrophy and improved glomerulosclerosis and glomerular hypertrophy in OLETF rats.
Conclusions:
- The angiotensin AT1 receptor plays a crucial role in the pathogenesis of cardiac and renal complications in NIDDM.
- Inhibition of the angiotensin AT1 receptor pathway offers a potential therapeutic strategy for managing NIDDM-related organ damage.
- These findings underscore the importance of targeting the renin-angiotensin system to prevent cardiovascular and renal sequelae in diabetes.