Comparative effects of angiotensin II receptor blockade (candesartan) with angiotensin-converting enzyme inhibitor (quinapril) in rats with dilated cardiomyopathy.
Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure, but their inhibitory actions on angiotensin I-induced increases in blood pressure in heart failure are not clear. Angiotensin I blocking and cardioprotective properties of the angiotensin II receptor blocker candesartan and the angiotensin-converting enzyme inhibitor quinapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Low-dose candesartan (0.5 mg/kg) showed the same angiotensin I blocking action as high-dose quinapril (20 mg/kg) in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (43/58, 74%) were divided into three groups and given quinapril at 20 mg/kg per day (group Q, n = 14), candesartan at 0.5 mg/kg per day (group C, n = 14) or vehicle alone (group V, n = 15). After oral administration for 1 month, four of 15 (27%) rats in group V and two of 14 (14%) in group C died. None of the animals in group Q died. Although angiotensin II levels of the blood and the left ventricle in group V [367 +/- 26 and 437 +/- 18% versus normal rats (group N)] were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). The left ventricular end-diastolic pressure and the area of myocardial fibrosis were lower, and the first derivative +/-dP/dt was higher in group Q (7.0 +/- 1.7 mmHg, 9 +/- 3% and +3451+/- 170/-3182 +/- 186 mmHg/s, respectively) than in group V (16.7 +/- 1.3 mmHg, 36 +/- 6% and +2601 +/- 235/-2156 +/- 257 mmHg/s, respectively) and in group C (11.2 +/- 2.0 mmHg, 26 +/- 4% and +3063 +/- 164/-2734 +/- 174 mmHg/s, respectively). Although levels of expression of transforming growth factor beta1 and collagen III mRNA in groupV (367 +/- 26 and 437 +/- 18% versus group N) were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). These results suggested that although low-dose candesartan can block increases in blood pressure with circulating angiotensin I to the same extent as high-dose quinapril, it does not confer sufficient protection against injury from the renin-angiotensin system in heart failure.
Watanabe
Kenichi
K
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, Japan. watanabe@niigata-pharm.ac.jp
Juan
Wen
W
Narasimman
Gurusamy
G
Ma
Meilei
M
Inoue
Mikio
M
Saito
Yuki
Y
Wahed
Mir I I
MI
Nakazawa
Mikio
M
Hasegawa
Go
G
Naito
Makoto
M
Tachikawa
Hitoshi
H
Tanabe
Naohito
N
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
Yamamoto
Tadashi
T
Yamaguchi
Kenichi
K
Takahashi
Toshihiro
T
D000803:Angiotensin I / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000503:physiopathology; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D000077583:Quinapril; D051381:Rats; D011917:Rats, Inbred Lew; D011945:Receptors, Angiotensin / Q000502:physiology; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007546:Isoquinolines; D011945:Receptors, Angiotensin; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D000803:Angiotensin I; D000077583:Quinapril; C081643:candesartan