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

Masami Hashimoto, Yoko Takada, Yusuke Takeuchi, Jiro Kasahara, Hiroaki Hisa, Yasufumi Shirasaki, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

We here assessed the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1- piperazinyl] ethyl]-5,6-dimethoxy-1-(4-imidazorylmethyl)-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.

Original languageEnglish
Pages (from-to)142-150
Number of pages9
JournalJournal of Pharmacological Sciences
Volume98
Issue number2
DOIs
Publication statusPublished - 2005 Jun

Keywords

  • Calmodulin antagonist
  • Calpain
  • Cardiomyocyte
  • Caspase-3
  • Coronary occlusion

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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