COX-2-derived prostacyclin mediates opioid-induced late phase of preconditioning in isolated rat hearts

Ken Shinmura, Maiko Nagai, Kayoko Tamaki, Masato Tani, Roberto Bolli

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Opioids confer biphasic (early and late) cardioprotection against myocardial infarction by opening mitochondrial ATP-sensitive K+ channels. It is unknown whether cyclooxygenase-2 (COX-2), which mediates ischemia-induced late preconditioning, also mediates opioidinduced cardioprotection. Isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW-373U86 (BW), a δ-opioid receptor agonist, was administered 1, 12, or 24 h before death. Recovery of left ventricular developed pressure (LVDP) after ischemia-reper- fusion improved when BW was administered 1 or 24 h before ischemia (control: 57 ± 8, BW 1 h: 75 ± 5, BW 24 h: 85 ± 6%) but not when it was administered 12 h before (60 ± 5%). Levels of 6-keto-PGF1a (a stable metabolite of PGI2) in coronary effluent after 20 min of reperfusion were higher with 24-h BW pretreatment than in controls (1,053 ± 92 vs. 724 ± 81 pg/ml), whereas 6-keto-PGF1a levels at baseline did not differ. Administration of a selective COX-2 inhibitor, NS-398, abolished the late phase of cardioprotection (recovery of LVDP, 53 ± 8%) and attenuated the increase in PGI2 (706 ± 138 pg/ml) but did not block the early phase of cardioprotection. The selective COX-1 inhibitor SC-560 did not affect either phase of protection. Western immunoblotting revealed upregulation of PGI2 synthase protein 24 h after BW administration without changes in COX-1 and COX-2 protein levels. In conclusion, the late (but not the early) phase of δ-opioid receptor-induced preconditioning is mediated by COX-2. A functional coupling between COX-2 and upregulated PGI2 synthase appears to underlie this cardioprotective phenomenon in the rat.

Original languageEnglish
Pages (from-to)H2534-H2543
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume283
Issue number6 52-6
DOIs
Publication statusPublished - 2002 Dec 1

Keywords

  • Myocardial ischemia
  • Opioid
  • Prostaglandin
  • Reperfusion injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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