ACE inhibitor and angiotensin II type 1 receptor blocker differently regulate ventricular fibrosis in hypertensive diastolic heart failure.
BACKGROUND
Promoted myocardial stiffening has a crucial role in the transition to overt diastolic heart failure (DHF) in hypertensive hearts and is attributed to progressive ventricular fibrosis. Previous studies revealed the effects of an angiotensin II type 1 receptor blocker (ARB) and an angiotensin-converting enzyme inhibitor (ACEI) on the synthesis and degradation of collagens in the other phenotype of heart failure, systolic heart failure, which has a different pathophysiology; however, little is known about their effects in DHF.


OBJECTIVE
To investigate effects of an ACEI and an ARB on the regulatory system of ventricular fibrosis in hypertensive DHF.


METHODS
Dahl salt-sensitive rats fed a diet containing 8% NaCl from age 7 weeks (DHF model) were divided into three groups: six untreated rats, six rats treated with a subdepressor dose of an ARB, candesartan cilexetil (1 mg/kg per day), from age 8 weeks, and six rats treated with a subdepress or dose of an ACEI, temocapril hydrochloride (0.2 mg/kg per day), from age 8 weeks. Six Dahl salt-sensitive rats fed on normal chow served as controls. Data were collected when animals were aged 20 weeks.


RESULTS
The administration of an ARB or an ACEI inhibited ventricular fibrosis to the same degree. The ACEI decreased the level of type I collagen mRNA, but the decrease was less than that induced by the ARB. The difference in collagen synthesis was probably cancelled out by that in degradation: both in-vitro and in-situ zymography showed that gelatinase activity was greater in the rats treated with the ACEI than in those treated with the ARB.


CONCLUSIONS
An ARB and an ACEI inhibited ventricular fibrosis through different mechanisms in hypertensive DHF.
Yamamoto
Kazuhiro
K
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka University, Suita, Japan. kazushiro@medone.med.osaka-u.ac.jp
Mano
Toshiaki
T
Yoshida
Junichi
J
Sakata
Yasushi
Y
Nishikawa
Nagahiro
N
Nishio
Mayu
M
Ohtani
Tomohito
T
Hori
Masatsugu
M
Miwa
Takeshi
T
Masuyama
Tohru
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D024042:Collagen Type I / Q000187:drug effects; D004452:Echocardiography; D005355:Fibrosis / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000150:complications*; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D013777:Tetrazoles / Q000494:pharmacology*; D013841:Thiazepines / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D024042:Collagen Type I; D013777:Tetrazoles; D013841:Thiazepines; C055603:temocapril hydrochloride; C077793:candesartan cilexetil