Effects of candesartan cilexetil (TCV-116) and enalapril in 5/6 nephrectomized rats.
The renal protective properties of candesartan cilexetil (TCV-116), an angiotensin II type 1 receptor antagonist (AT1A), and enalapril, an angiotensin I converting enzyme inhibitor (ACEI), were investigated in 5/6 nephrectomized (NX) rats. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were administered orally to 5/6 NX rats for four weeks (during the early phase of disease development) or 16 weeks (through the late phase). In vehicle-treated rats, proteinuria, glomerulosclerosis, interstitial mononuclear cell (MNC) infiltration and interstitial fibrosis developed. Moreover, immunohistological studies showed enhanced expression of transforming growth factor-beta 1 (TGF-beta 1) in the injured glomeruli. Both drugs inhibited these adverse changes in the early phase. In the late phase, the progressive proteinuria, interstitial MNC infiltration were attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta 1 and the interstitial fibrosis, while enalapril did not. Candesartan cilexetil and enalapril showed comparable hypotensive effects after the 16-week administration. These results indicate that candesartan cilexetil shows a more potent protective effect than enalapril against the progression of renal injury in the late phase. Thus, an AT1A might be more useful than an ACEI for the treatment of patients with chronic renal failure.
Noda
M
M
Pharmaceutical Research Laboratories II, Takeda Chemical Industries Ltd., Osaka, Japan. Noda_Masakuni@takeda.co.jp
Fukuda
R
R
Matsuo
T
T
Ohta
M
M
Nagano
H
H
Imura
Y
Y
Nishikawa
K
K
Shibouta
Y
Y
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018450:Disease Progression; D004656:Enalapril / Q000494:pharmacology*; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D004656:Enalapril; C077793:candesartan cilexetil