Benidipine Reduces Myocardial Infarct Size Involving Reduction of Hydroxyl Radicals and Production of Protein Kinase C-Dependent Nitric Oxide in Rabbits

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Abstract
Japanese white rabbits underwent 30 minutes of ischemia and 48 hours of reperfusion. Benidipine (3 or 10 μg/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 × 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 μg/kg: 29.0 ± 2.7%, n = 8, 10 μg/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.

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