ANGIOTENSIN BLOCKADE IMPROVES CARDIAC AND RENAL COMPLICATIONS OF TYPE-II DIABETIC RATS

Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new model of h uman 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-con verting enzyme inhibitor, 1 or 10 mg/kg), E4177 (an angiotensin AT(1) receptor antagonist, 10 mg/kg), or vehicle for 26 or 40 weeks (from th e age of 20 to 46 or 60 weeks). Cardiac mRNAs were measured by Norther n blot analysis, and the thickening of the coronary arterial wall and the degree of perivascular fibrosis were determined by an image analyz er. Cilazapril or E4177 did not significantly affect body weight or pl asma glucose and insulin levels of OLETF rats, indicating the minor ef fects on diabetes itself. However, both drugs significantly and simila rly 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 su ppression of cardiac transforming growth factor-beta 1 expression. Bot h drugs suppressed not only the increase in left ventricular weight bu t also the downregulation of cardiac alpha-myosin heavy chain expressi on in OLETF rats. Glomerulosclerosis and glomerular hypertrophy in OLE TF rats were improved by cilazapril and E4177 to a comparable extent. These results, taken together with the fact that OLETF rats show norma l plasma renin levels, support that the AT(1) receptor is involved in the pathogenesis of cardiac and renal complications in NIDDM.