Effects of captopril and telmisartan on matrix metalloproteinase-2 and -9 expressions and development of left ventricular fibrosis induced by isoprenaline in rats.
The aim of this study was to clarify the effects of renin-angiotensin system (RAS) blockade by captopril, an angiotensin converting enzyme inhibitor, and telmisartan, an angiotensin II type 1 receptor antagonist, on matrix metalloproteinase (MMP)-2 and MMP-9 expressions and development of left ventricular (LV) fibrosis induced by isoprenaline in rats. Rats were treated with subcutaneous injection of isoprenaline (5 mg/kg/d) and with oral administration of captopril (30 mg/kg/d) or telmisartan (3 mg/kg/d) for 1 or 7 d. Hearts were excised at the day 2 and day 8. Degree of fibrosis was evaluated by Azan staining. MMP-2 and MMP-9 expressions were analyzed by Western blotting. Localization of MMP-9 expression in LV section was detected by immunohistochemical staining. At the day 8, myocardial fibrosis was observed in LV section from isoprenaline-treated rats. Captopril but not telmisartan significantly enhanced the isoprenaline-induced myocardial fibrosis. MMP-9 expression at the day 2 and MMP-2 expression at the day 8 increased significantly in LV from isoprenaline-treated rats. Captopril had no influence on the MMP-2 expression, but significantly augmented the isoprenaline-induced MMP-9 expression. Telmisartan had no effect on the isoprenaline-induced MMP-2 and MMP-9 expressions. In immunohistochemical staining, MMP-9 positive-interstitial cells were extensively observed in LV sections from isoprenaline + captopril-treated rats at the day 2. The present study reveals that RAS blockade by captopril and telmisartan does not have suppressive effects on isoprenaline-induced MMP-2 and MMP-9 expressions as well as LV fibrosis. Furthermore, captopril may enhance LV fibrosis through promoting isoprenaline-induced MMP-9 expression in cardiac interstitial cells.
Okada
Muneyoshi
M
Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori, Japan. mokada@vmas.kitasato-u.ac.jp
Kosaka
Natsuko
N
Hoshino
Yoshikazu
Y
Yamawaki
Hideyuki
H
Hara
Yukio
Y
D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001565:Benzoates / Q000008:administration & dosage*; D002216:Captopril / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D000077333:Telmisartan; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*
D001562:Benzimidazoles; D001565:Benzoates; D002216:Captopril; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007545:Isoproterenol; D000077333:Telmisartan