Kinin and angiotensin II receptor antagonists in rats with chronic renal failure: chronic effects on cardio- and renoprotection of angiotensin converting enzyme inhibitors.
OBJECTIVE
To assess the potential of the kallikrein-kinin and renin-angiotensin systems in mediating the cardio- and renoprotective effects of angiotensin converting enzyme (ACE) inhibitors in rats with chronic renal failure.


METHODS
Spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats subjected to five-sixths nephrectomy were randomly assigned to treatment with vehicle, a kinin antagonist (Hoe 140) or an ACE inhibitor (cilazapril) or both drugs, intraperitoneally via osmotic minipumps for 4 weeks. In addition, the effects of a chronic infusion of a specific angiotensin receptor antagonist (losartan) alone or in combination with an ACE inhibitor (enalapril) were also investigated in nephrectomized SHR for 2 weeks.


RESULTS
In nephrectomized SHR and WKY rats, cilazapril alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine. In nephrectomized SHR, Hoe 140 alone or cilazapril in combination with Hoe 140 (7 or 70 mu g/kg per day) induced no changes in these parameters, other than those associated with the effects of cilazapril alone. In nephrectomized WKY rats, cilazapril in combination with Hoe 140 (70 mu g/kg per day) slightly, but not significantly, attenuated the antihypertensive effect of cilazapril but did not affect the other parameters. These results were confirmed by morphological analysis of kidneys. All the drug regimens provided effective protection against an increase in focal glomerular sclerosis. Enalapril did not modify the antihypertensive and renoprotective effects of losartan in nephrectomized SHR.


CONCLUSIONS
The present results indicate that the kallikrein-kinin system might not be a major factor in the cardio- and renoprotective effects of ACE inhibitors in rats with chronic renal failure.
Section of Internal Medicine & Disability Prevention, Disability Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
M
M
Kohzuki
M
M
Kanazawa
P F
PF
Liu
M
M
Kamimoto
K
K
Yoshida
T
T
Saito
M
M
Yasujima
T
T
Sato
K
K
Abe
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017315:Cilazapril / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood*; D004359:Drug Therapy, Combination; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009392:Nephrectomy; D011507:Proteinuria / Q000652:urine*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D017315:Cilazapril; C065679:icatibant; D003404:Creatinine; D001920:Bradykinin