Cytoprotective Effect of 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e) Against Ischemia/Reperfusion-Induced Injury in Rat Heart Involves Inhibition of Fodrin Breakdown and Protein Tyrosine Nitration

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  • Hashimoto Masami
    Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
  • Takada Yoko
    Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
  • Takeuchi Yusuke
    Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
  • Kasahara Jiro
    Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
  • Hisa Hiroaki
    Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
  • Shirasaki Yasufumi
    New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd.
  • Fukunaga Kohji
    Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences Tohoku University 21st Century COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation"

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We here assessed the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, on infarct size in the rat heart subjected to ischemia/reperfusion. Rats were subjected to a 30-min coronary occlusion followed by a 24-h reperfusion. DY-9760e was intravenously infused for 20 min, starting at 20 min after coronary occlusion. Treatment with DY-9760e (10 mg/kg) significantly reduced the infarct size in the risk area assessed by Evans Blue/TTC (triphenyltetrazolium chloride) staining. DY-9760e treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. DY-9760e significantly inhibited fodrin breakdown and caspase-3 activation. The inhibitory effect of DY-9760e on the fodrin breakdown was prominent in the rim rather than in the center of the risk area. DY-9760e also blocked protein tyrosine nitration associated with infarction. These results suggest that the cardioprotective effect of DY-9760e involved inhibition of calpain/caspase activation and protein tyrosine nitration.<br>

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