JTV-519, a novel cardioprotective agent, improves the contractile recovery after ischaemia-reperfusion in coronary perfused guinea-pig ventricular muscles

Ken Ichiro Ito, Sakuji Shigematsu, Toshiaki Sato, Takako Abe, Yulong Li, Makoto Arita

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

1. A newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective. However, the precise mechanism underlying the cardioprotective effect of this drug is unknown. 2. Coronary-perfused guinea-pig ventricular muscles were subjected to 20-min no-flow ischaemia followed by 60-min reperfusion (I/R). I/R significantly decreased the contraction in untreated preparations (control group, 34 ± 4% of baseline value, n = 6). Brief administration of JT (1.0 μM) prior to ischaemia significantly improved the postischaemic contractile recovery (63 ± 5% of baseline value, n = 4), as compared to the control group. 3. JT (1.0 μM) slightly prolonged action potential duration before ischaemia and induced conduction disturbance (2:1 block) after the initiation of ischaemia. 4. The cardioprotective effect of JT was antagonized by chelerythrine (CH, 5.0 μM), an inhibitor of protein kinase C (PKC) or by 5-hydroxydecanoic acid (5-HD, 400 μM), an inhibitor of mitochondrial ATP-sensitive K+ (K(ATP)) channels. 5. These results suggest that the protective effect of JT is due to the opening of mitochondrial K(ATP) channels, which, in turn, is linked to PKC activation.

Original languageEnglish (US)
Pages (from-to)767-776
Number of pages10
JournalBritish Journal of Pharmacology
Volume130
Issue number4
DOIs
StatePublished - 2000

Keywords

  • Mitochondria
  • Pharmacological preconditioning
  • Protein kinase C

ASJC Scopus subject areas

  • Pharmacology

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