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- Title
Antiapoptotic mechanisms of benidipine in the ischemic/reperfused heart.
- Authors
Hui-Rong Liu; Feng Gao; Ling Tao; Wen-Li Yan; Erhe Gao; Christopher, Theodore A.; Lopez, Bernard L.; Aihua Hu; Ma, Xin L.
- Abstract
1: Considerable evidence indicates that calcium plays a critical role in apoptosis. We have previously shown that benidipine, a vasodilatory calcium channel blocker, attenuates postischemia myocardial apoptosis. The present study was designed to determine the mechanisms by which benidipine exerts its antiapoptotic effect. 2: Adult male rats were subjected to 30?min of ischemia followed by 3?h of reperfusion. Rats were randomized to receive either vehicle or benidipine (10?µg?kg-1, i.v.) 10?min before reperfusion. 3: Compared with rats receiving vehicle, those rats treated with benidipine had reduced postischemic myocardial apoptosis as evidenced by decreased TUNEL-positive staining (8.4±1.2 vs 15.3±1.3%, P<0.01) and caspase-3 activity (1.94±0.25 vs 3.43±0.29, P<0.01). 4: Benidipine treatment significantly reduced mitochondrial cytochrome c release and caspase-9 activation, but had no effect on caspase-8 activation, suggesting that benidipine exerts its antiapoptotic effect by inhibiting the mitochondrial-mediated, but not death receptor-mediated, apoptotic pathway. 5: Benidipine treatment not only increased the maximal activity of ERK1/2 at 10?min after reperfusion, but also prolonged the duration of ERK1/2 activation. Benidipine treatment had no significant effect on other apoptotic regulating molecules, such as p38 MAPK. 6: Taken together, our present study demonstrated for the first time the differential regulation of a calcium channel blocker. Benidipine tilted the balance between ERK1/2 and p38 MAPK toward an antiapoptotic state, decreased mitochondrial cytochrome c release, reduced caspase-9 activation, and attenuated subsequent caspase-3 activation and postischemic myocardial apoptosis.British Journal of Pharmacology (2004) 142, 627-634. doi:10.1038/sj.bjp.0705847
- Subjects
MYOCARDIAL infarction; APOPTOSIS; CALCIUM in the body; CALCIUM antagonists; ISCHEMIA; REPERFUSION injury
- Publication
British Journal of Pharmacology, 2004, Vol 142, Issue 4, p627
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0705847