Antihypertensive and renal-protective effects of losartan in streptozotocin diabetic rats.
OBJECTIVE
To assess the renal benefits of a specific angiotensin II receptor antagonist, losartan, in diabetic rats with renal impairment.


METHODS
Uninephrectomized streptozotocin diabetic spontaneously hypertensive rats (SHR) were randomly assigned to receive vehicle, or to receive losartan or captopril, or both, intraperitoneally via osmotic minipumps for 8 weeks.


RESULTS
Blood pressure and urinary protein 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. Simultaneous administration of captopril and losartan did not enhance the antihypertensive effects of losartan treatment or captopril treatment. Furthermore, losartan treatment, captopril treatment and losartan + captopril treatment all significantly decreased urinary protein excretion, urinary albumin excretion and serum creatinine to the same extent. These effects were sustained for the entire experimental period and were not associated with any significant changes in body weight, urine volume, urine sugar and urinary electrolytes excretion. These results were confirmed by morphological analysis of kidneys in each group of rats. Losartan treatment, captopril treatment and losartan+captopril treatment all significantly and effectively protected against an increase in the percentage of focal glomerular sclerosis. Losartan treatment 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 captopril-treated group.


CONCLUSIONS
These results indicate that hypertension could accelerate diabetic renal impairment and that losartan has antihypertensive and renoprotective effects in this rat model. They also suggest that the antihypertensive and renoprotective effects of captopril treatment in this rat model are caused mainly by inhibition of angiotensin II production rather than stimulation of the kallikrein-kinin system or of vasodilator prostaglandins. The difference in potency between losartan treatment and captopril treatment to attenuate the increase in heart weight: body weight ratio might partly explain the existence in the heart of angiotensin-forming pathways, which are not dependent on angiotensin converting enzyme.
Kohzuki
M
M
Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Yasujima
M
M
Kanazawa
M
M
Yoshida
K
K
Fu
L P
LP
Obara
K
K
Saito
T
T
Abe
K
K
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan; D008297:Male; D009929:Organ Size; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D002216:Captopril; D019808:Losartan