Effects of eplerenone on heart and kidney in two-kidney, one-clip rats.
BACKGROUND
The role of aldosterone has been less investigated compared to the renin-angiotensin-aldosterone system in renovascular hypertension. The purpose of the present study was to compare the effects of a selective aldosterone receptor blocker, eplerenone (EP), and an angiotensin II receptor type 1 antagonist (AT1RA), losartan (LO) on cardiac and renal damage produced by two-kidney, one-clip (2K-1C) renovascular hypertension in rats.


METHODS
Wistar rats (n = 48) were placed on one of six groups. Group 1 received sham operation. From group 2 to 6, all rats were made as 2K-1C renovascular hypertension. Group 2 received vehicle. Group 3 orally received 100 mg/kg/day of EP from the initiation of the study. Group 4 received 100 mg/kg/day of LO, from the initiation of the study. Groups 5 and 6 received EP and LO from the 4th week after the clipping respectively. Systolic blood pressure (SBP) and urinary protein excretion (UPE) were measured before and every 2 weeks. The remnant kidney was obtained for histopathological analysis and for measurement of endothelial cell nitric oxide synthase (ecNOS) gene expression (GE).


RESULTS
SBP increased in the placebo group (132.1 +/- 2.4 vs. 115.0 +/- 0.6 mm Hg in sham group at week 10, p = 0.019). Treatment with LO or EP from the beginning of the study decreased SBP significantly as measured in the sham group at week 10. The placebo group developed significant UPE (21.7 +/- 1.9 mg/day) compared with the sham group (13.4 +/- 0.8 mg/day, p < 0.05). Treatment with both LO (12.5 +/- 1.5 mg/day, p < 0.01 vs. placebo) and EP (14.8 +/- 1.0 mg/ day, p < 0.05 vs. placebo) significantly decreased UPE. On the other hand, the late start of treatment with EP failed to decrease the increased UPE. UPEs were not significantly different between the LO- and EP-treated groups throughout the study. There was no significant pathological change in heart and kidney in all groups. In heart, ecNOS GE was significantly increased in the EP-treated (from the beginning of the study) rats compared with placebo group (0.47 +/- 0.01 vs. 0.43 +/- 0.01, p < 0.05). LO did not have an effect on ecNOS GE in heart. In aorta, ecNOS GE was significantly increased in the two EP-treated groups compared with the placebo group (0.22 +/- 0.01, 0.22 +/- 0.02 vs. 0.15 +/- 0.01, p < 0.05, respectively). LO also did not have an effect on ecNOS GE in aorta. In kidney, ecNOS GE was significantly increased in the LO group (from the beginning of the study) and two EP-treated groups compared with placebo.


CONCLUSIONS
This study demonstrated that EP treatment significantly reduced SBP and UPE compared with placebo in both development and established 2K-1C renovascular hypertension. EP was as effective as LO in lowering the blood pressure of this renin-dependent animal model.
Hao
Lirong
L
Department of Nephrology, Saitama Medical School, Saitama, Japan. iromichi@saitama-med.ac.jp
Kanno
Yoshihiko
Y
Fukushima
Rie
R
Watanabe
Yusuke
Y
Ishida
Yuji
Y
Suzuki
Hiromichi
H
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D000077545:Eplerenone; D006321:Heart / Q000187:drug effects*; D006978:Hypertension, Renovascular / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D019808:Losartan / Q000627:therapeutic use; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone; D019808:Losartan