Ischemic preconditioning increases the bioavailability of cardiac enkephalins

Antoine Younès, Salvatore Pepe, Darice Yoshishige, James L. Caffrey, Edward Lakatta

Research output: Contribution to journalArticle

Abstract

Growing evidence suggests that cardiac enkephalins and their receptors are involved in ischemic preconditioning (IPC). Because there is no evidence for vesicular storage of small bioactive enkephalins in the heart, studies were designed to test the hypothesis that ischemia depletes cardiac enkephalins and that IPC preserves the same enkephalins by accelerating their processing from the larger proenkephalin precursor (PEP) pool. The precursors and two bioactive representatives, Met-enkephalin (ME) and Met-enkephalin-Arg-Phe (MEAP), were separated by size-exclusion chromatography and quantified by radioimmunoassay. Isolated perfused rat hearts were prepared and exposed to global ischemia. After 30 min of global ischemia and 40 min of reflow, the PEP pool was reduced (from 17.99 ± 1.52 to 14.20 ± 2.38 pmol/g wet wt), MEAP increased by 53%, and ME declined by 68%. The sum of the two smaller peptides was unchanged (9.78 ± 0.83 vs. 9.33 ± 2.81). Thus the total enkephalin peptide content was not altered (27.77 ± 1.69 vs. 24.10 ± 4.75). Peptide distribution after ischemia and reflow was also unaltered by pretreatment with peptidase inhibitors. However, when the hearts were preconditioned, the PEP pool remained significantly lower and both of the bioactive peptides, MEAP and ME, were elevated (+49% and +86%, respectively). The decline in the PEP pool was prevented by peptidase inhibition and the rise in MEAP was exaggerated. In separate protocols, synthetic enkephalins (ME, MEAP, and Leuenkephalin) were added to the coronary inflow before 30 min of global ischemia and throughout the subsequent reflow. The added enkephalins (10-8 M) had no inotropic effect on baseline function but completely prevented the mechanical dysfunction observed in untreated controls during reflow. Thus IPC appears to increase available bioactive enkephalins (MEAP + ME) within the heart by enhancing synthesis of precursors and their subsequent processing from the PEP pool.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number4 58-4
DOIs
StatePublished - Oct 2005
Externally publishedYes

Fingerprint

Methionine Enkephalin
Ischemic Preconditioning
Enkephalins
Biological Availability
Ischemia
Peptides
Opioid Receptors
Protease Inhibitors
Radioimmunoassay
Gel Chromatography
Peptide Hydrolases
proenkephalin

Keywords

  • Heart
  • Opioid peptide processing
  • Opioid peptides

ASJC Scopus subject areas

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

Cite this

Ischemic preconditioning increases the bioavailability of cardiac enkephalins. / Younès, Antoine; Pepe, Salvatore; Yoshishige, Darice; Caffrey, James L.; Lakatta, Edward.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 289, No. 4 58-4, 10.2005.

Research output: Contribution to journalArticle

Younès, Antoine ; Pepe, Salvatore ; Yoshishige, Darice ; Caffrey, James L. ; Lakatta, Edward. / Ischemic preconditioning increases the bioavailability of cardiac enkephalins. In: American Journal of Physiology - Heart and Circulatory Physiology. 2005 ; Vol. 289, No. 4 58-4.
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AB - Growing evidence suggests that cardiac enkephalins and their receptors are involved in ischemic preconditioning (IPC). Because there is no evidence for vesicular storage of small bioactive enkephalins in the heart, studies were designed to test the hypothesis that ischemia depletes cardiac enkephalins and that IPC preserves the same enkephalins by accelerating their processing from the larger proenkephalin precursor (PEP) pool. The precursors and two bioactive representatives, Met-enkephalin (ME) and Met-enkephalin-Arg-Phe (MEAP), were separated by size-exclusion chromatography and quantified by radioimmunoassay. Isolated perfused rat hearts were prepared and exposed to global ischemia. After 30 min of global ischemia and 40 min of reflow, the PEP pool was reduced (from 17.99 ± 1.52 to 14.20 ± 2.38 pmol/g wet wt), MEAP increased by 53%, and ME declined by 68%. The sum of the two smaller peptides was unchanged (9.78 ± 0.83 vs. 9.33 ± 2.81). Thus the total enkephalin peptide content was not altered (27.77 ± 1.69 vs. 24.10 ± 4.75). Peptide distribution after ischemia and reflow was also unaltered by pretreatment with peptidase inhibitors. However, when the hearts were preconditioned, the PEP pool remained significantly lower and both of the bioactive peptides, MEAP and ME, were elevated (+49% and +86%, respectively). The decline in the PEP pool was prevented by peptidase inhibition and the rise in MEAP was exaggerated. In separate protocols, synthetic enkephalins (ME, MEAP, and Leuenkephalin) were added to the coronary inflow before 30 min of global ischemia and throughout the subsequent reflow. The added enkephalins (10-8 M) had no inotropic effect on baseline function but completely prevented the mechanical dysfunction observed in untreated controls during reflow. Thus IPC appears to increase available bioactive enkephalins (MEAP + ME) within the heart by enhancing synthesis of precursors and their subsequent processing from the PEP pool.

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