title: Benidipine reduces myocardial infarct size involving reduction of hydroxyl radicals and production of protein kinase C-dependent nitric oxide in rabbits.
abstract: Japanese white rabbits underwent 30 minutes of ischemia and 48 hours of reperfusion. Benidipine (3 or 10 microg/kg, i.v.) was administered 10 minutes before ischemia with and without pretreatment with L-NAME (10 mg/kg, i.v., a NOS inhibitor), chelerythrine (5 mg/kg, i.v., a PKC blocker) or 5-HD (5 mg/kg, i.v. a mitochondrial KATP channel blocker), genistein (5 mg/kg, i.v. a protein tyrosin kinase blocker). SNAP (2.5 mg/kg/min x 70 minutes, i.v., an NO donor) was also administered 10 minutes before ischemia. Benidipine significantly reduced the infarct size in a dose-dependent manner (3 microg/kg: 29.0 +/- 2.7%, n = 8, 10 microg/kg: 23.0 +/- 2.4%, n = 10) compared with the control (41.6 +/- 3.3%, n = 10). This effect was completely blocked by L-NAME (39.9 +/- 3.6%, n = 8) and chelerythrine (35.5 +/- 2.4%, n = 8) but not by 5-HD (23.0 +/- 2.4%, n = 10) or genistein (24.6 +/- 3.1%, n = 10). SNAP also reduced the infarct size (24.6 +/- 3.1%, n = 8). Benidipine significantly increased the expression of eNOS mRNA at 30 minutes after reperfusion and significantly increased the expression of eNOS protein at 3 hours after reperfusion in the ischemic area of the left ventricle. Benidipine and SNAP significantly decreased myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, during ischemia and reperfusion. Benidipine increased myocardial interstitial NOx levels, which effect was blocked by chelerythrine, during 0 to 30 minutes and 150 to 180 minutes after reperfusion. Benidipine reduces the infarct size through PKC-dependent production of nitric oxide and decreasing hydroxyl radicals but not through involving protein tyrosine kinase or mitochondrial KATP channels in rabbits.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Ningyuan
authors.initials: N
authors.lastname: Wang
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Xue-Hai
authors.initials: XH
authors.lastname: Chen
authors.forename: Masazumi
authors.initials: M
authors.lastname: Arai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uno
authors.forename: ChuanJiang
authors.initials: C
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Misao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000502:physiology*; D011817:Rabbits
chemical_list: D004095:Dihydropyridines; D009569:Nitric Oxide; D017665:Hydroxyl Radical; C061004:benidipine; D011493:Protein Kinase C