ANTIHYPERTENSIVE AND RENAL-PROTECTIVE EFFECTS OF LOSARTAN IN STREPTOZOTOCIN-DIABETIC RATS

Objective: To assess the renal benefits of a specific angiotensin II r eceptor antagonist, losartan, in diabetic rats with renal impairment. Design and methods: Uninephrectomized streptozotocin diabetic spontane ously hypertensive rats (SHR) were randomly assigned to receive vehicl e, or to receive losartan or captopril, or both, intraperitoneally via osmotic minipumps for 8 weeks. Results: Blood pressure and urinary pr otein excretion in the diabetic SHR increased progressively during the experimental period. Both captopril treatment and losartan treatment completely blocked the development of hypertension in diabetic SHR. Si multaneous administration of captopril and losartan did not enhance th e antihypertensive effects of losartan treatment or captopril treatmen t. Furthermore, losartan treatment, captopril treatment and losartan captopril treatment all significantly decreased urinary protein excre tion, urinary albumin excretion and serum creatinine to the same exten t. These effects were sustained for the entire experimental period and were not associated with any significant changes in body weight, urin e volume, urine sugar and urinary electrolytes excretion. These result s were confirmed by morphological analysis of kidneys in each group of rats. Losartan treatment, captopril treatment and losartan + captopri l treatment all significantly and effectively protected against an inc rease in the percentage of focal glomerular sclerosis. Losartan treatm ent and captopril treatment both significantly attenuated the increase in heart weight:body weight ratio. The heart weight:body weight ratio in the losartan-treated group was significantly lower than in the cap topril-treated group. Conclusions: These results indicate that hyperte nsion could accelerate diabetic renal impairment and that losartan has antihypertensive and renoprotective effects in this rat model. They a lso suggest that the antihypertensive and renoprotective effects of ca ptopril treatment in this rat model are caused mainly by inhibition of angiotensin II production rather than stimulation of the kallikrein-k inin system or of vasodilator prostaglandins. The difference in potenc y between losartan treatment and captopril treatment to attenuate the increase in heart weight:body weight ratio might partly explain the ex istence in the heart of angiotensin-forming pathways, which are not de pendent on angiotensin converting enzyme.