Different effects of calcium channel blockers on matrix metalloproteinase-2 expression in cultured rat cardiac fibroblasts.
The cardiac effects of calcium channel blockers (CCBs) related to cardiac remodeling are inconsistent. Matrix metalloproteinases (MMPs) contribute to tissue remodeling. Cardiac fibroblasts play an important role in the regulation of collagen degradation by MMPs. Using gelatin zymography, Western blotting, Griess reagent, and a calcium kit-fluo 3, we investigated the effects of nifedipine, verapamil, diltiazem, and amlodipine on MMP-2 expression and further elucidate the mechanisms in cultured rat cardiac fibroblasts. Nifedipine increased and amlodipine decreased the expression of MMP-2; however, neither verapamil nor diltiazem altered MMP-2 expression. Nifedipine also increased nitrite production, and this increase was blunted by a nitric oxide (NO) synthases inhibitor (L-NAME). Nifedipine-induced MMP-2 expression was also blunted by L-NAME. An NO donor (sodium nitroprusside) induced MMP-2 expression. Data indicated that nifedipine might increase MMP-2 expression through a possible NO-dependent pathway. Amlodipine had no influence on nitrite production. The amlodipine-induced decrease of MMP-2 expression was abolished by two protein tyrosine kinase inhibitors, genistein and herbimycin A, indicating that amlodipine might decrease MMP-2 expression through a possible protein tyrosine kinase pathway. None of the four CCBs could alter the fluoscence intensity of fluo 3, indicating that the effects of CCBs on MMP-2 expression were independent of the variation in intracellular C2+ concentration. Our findings revealed that different CCBs exerted different effects on MMP-2 expression in cardiac fibroblasts.
Yue
Hong
H
First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Uzui
Hiroyasu
H
Shimizu
Hiromasa
H
Nakano
Akira
A
Mitsuke
Yasuhiko
Y
Ueda
Takanori
T
Lee
Jong-Dae
JD
D017311:Amlodipine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000187:drug effects*; D061965:Matrix Metalloproteinase Inhibitors; D009206:Myocardium / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017828:Rifabutin / Q000031:analogs & derivatives; D014700:Verapamil / Q000494:pharmacology
D016227:Benzoquinones; D002121:Calcium Channel Blockers; D047029:Lactams, Macrocyclic; D061965:Matrix Metalloproteinase Inhibitors; D047428:Protein Kinase Inhibitors; D011809:Quinones; D009599:Nitroprusside; D017311:Amlodipine; D017828:Rifabutin; D009569:Nitric Oxide; C020754:herbimycin; D014700:Verapamil; D019833:Genistein; D020778:Matrix Metalloproteinase 2; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester