Fasudil attenuates myocardial fibrosis in association with inhibition of monocyte/macrophage infiltration in the heart of DOCA/salt hypertensive rats.
OBJECTIVE
To determine the effects of fasudil, a Rho-kinase inhibitor, on mineralocorticoid-induced myocardial remodeling, we investigated whether fasudil would suppress myocardial fibrosis and inflammation in deoxycorticosterone-acetate (DOCA)/salt hypertensive rats.


METHODS
Sprague-Dawley rats treated with DOCA combined with 1% NaCl and 0.2% KCl in the drinking water after receiving left nephrectomy were given fasudil (10 mg/kg/day; n = 20) or vehicle (n = 20). Systolic blood pressure (SBP) was measured biweekly. Myocardial monocyte/macrophage infiltration and myocardial fibrosis were determined histologically. Expressions of mRNA of procollagen I (PI), procollagen III (PIII), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, type-1 plasminogen activator inhibitor (PAI-1), transforming growth factor (TGF)-beta1, and c-fos were determined.


RESULTS
SBP was significantly increased on day 14 after treatment with DOCA/salt. Extent of interstitial and perivascular fibrosis was significantly increased on day 28. Expressions of mRNA of PI, PIII, MCP-1, IL-6, PAI-1, TGF-beta1, and c-fos were significantly increased on day 14. Although SBP did not differ between the fasudil and vehicle groups, extent of monocyte/macrophage infiltration and fibrosis was attenuated in the fasudil group. Expressions of mRNA of these factors except TGF-beta1 were also attenuated.


CONCLUSIONS
Fasudil attenuates myocardial fibrosis possibly via suppression of monocyte/macrophage infiltration of the heart in DOCA/salt hypertensive rats.
Ishimaru
Kazuhiro
K
Second Department of Internal Medicine, University of Toyama, Toyama, Japan.
Ueno
Hitoshi
H
Kagitani
Satoshi
S
Takabayashi
Daisuke
D
Takata
Masanobu
M
Inoue
Hiroshi
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000235:genetics; D003900:Desoxycorticosterone; D004719:Endomyocardial Fibrosis / Q000188:drug therapy*; D024022:Fibrillar Collagens / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000150:complications*; D007249:Inflammation / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008901:Mineralocorticoids; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary
D016207:Cytokines; D024022:Fibrillar Collagens; D008901:Mineralocorticoids; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil