Comparative analysis of the cardioprotective properties of opioid receptor agonists in a rat model of myocardial infarction

Leonid N. Maslov, Yury B. Lishmanov, Peter R. Oeltgen, Eva I. Barzakh, Andrey V. Krylatov, Natalia V. Naryzhnaya, Jian Ming Pei, Stephen A. Brown

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objectives: This study was conducted to test the hypothesis that opioid receptor (OR)-mediated cardioprotection is agonist specific when administered prior to coronary artery occlusion and reperfusion in a rat model. Methods: Anesthetized open-chest male Wistar rats were subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. Opioid agonists were infused 15 minutes prior to coronary artery occlusion. Two control groups and 15 opioid-treated groups were studied. Controls were infused with either saline alone (n = 16) or dimethyl sulfoxide plus hydroxypropyl-β-cyclodextrin in saline (n = 19). The μ-selective agonist DAMGO was infused at either 150 nmol/kg (n = 15) or 1500 nmol/kg (n = 14), and dermorphin-H was infused at 150 nmol/kg (n = 14). The δ1-selective agonist d-Pen2,5 enkephalin (DPDPE) was infused at 150 nmol/kg (n = 16) or 1500 nmol/kg (n = 14). The δ2-selective agonists deltorphin II (n = 16), deltorphin-Dvariant (n = 15), and deltorphin-E (n = 14) were infused at 150 nmol/kg. The selective κ1 opioid agonist U-50488 was infused at 240 nmol/kg (n = 14), 1500 nmol/kg (n = 14), and 2,400 nmol/kg (n = 14). The selective κ2 opioid agonist GR-89696 was infused at 150 nmol/kg (n = 14) and 1500 nmol/kg (n = 15). Orphinan FQ (nociceptin), also referred to as OR-like 1 (ORL1), was infused at 220 nmol/kg (n = 15) and 1500 nmol/kg (n = 15). The infarct size/area at risk (IS/AAR) ratio was determined after reperfusion by negative staining with patent blue violet dye. Hemodynamic parameters including heart rate, mean arterial blood pressure (MAP), and rate pressure product (RPP) were determined. Results: Pretreatment with the δ2 OR agonist deltorphin II (150 nmol/kg) significantly reduced the IS/AAR ratio, while deltorphin-Dvariant and deltorphin-E did not exhibit an infarct-sparing effect at that treatment dose. Activation of δ1 OR by DPDPE, κ1 OR by U-50488, κ2 OR by GR-89696, μ OR by DAMGO, dermorphin-H, and nociceptin had no effect on the IS/AAR ratio. U-50488 at 2,400 nmol/L induced a bradycardic effect. All other opioids had no effect on hemodynamic parameters at the doses tested. Conclusions: Peripheral δ2 OR activation by deltorphin II induces infarct size reduction in this animal model. Agonists of μ, δ1, κ1, κ2, and nociceptin receptors at the doses tested did not induce cardiac tolerance to ischemia/reperfusion injury in vivo.

Original languageEnglish
Pages (from-to)1239-1246
Number of pages8
JournalAcademic Emergency Medicine
Volume17
Issue number11
DOIs
Publication statusPublished - Nov 2010

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Opioid Receptors
Myocardial Infarction
Opioid Analgesics
(trans)-Isomer 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide
Coronary Occlusion
D-Penicillamine (2,5)-Enkephalin
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Coronary Vessels
Odds Ratio
Reperfusion
Arterial Pressure
Hemodynamics
Negative Staining
Myocardial Reperfusion
Enkephalins
Cyclodextrins
Dimethyl Sulfoxide
Reperfusion Injury
Wistar Rats
Coloring Agents

Keywords

  • heart
  • ischemia
  • opioid receptors
  • reperfusion

ASJC Scopus subject areas

  • Emergency Medicine

Cite this

Comparative analysis of the cardioprotective properties of opioid receptor agonists in a rat model of myocardial infarction. / Maslov, Leonid N.; Lishmanov, Yury B.; Oeltgen, Peter R.; Barzakh, Eva I.; Krylatov, Andrey V.; Naryzhnaya, Natalia V.; Pei, Jian Ming; Brown, Stephen A.

In: Academic Emergency Medicine, Vol. 17, No. 11, 11.2010, p. 1239-1246.

Research output: Contribution to journalArticle

Maslov, Leonid N. ; Lishmanov, Yury B. ; Oeltgen, Peter R. ; Barzakh, Eva I. ; Krylatov, Andrey V. ; Naryzhnaya, Natalia V. ; Pei, Jian Ming ; Brown, Stephen A. / Comparative analysis of the cardioprotective properties of opioid receptor agonists in a rat model of myocardial infarction. In: Academic Emergency Medicine. 2010 ; Vol. 17, No. 11. pp. 1239-1246.
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TY - JOUR

T1 - Comparative analysis of the cardioprotective properties of opioid receptor agonists in a rat model of myocardial infarction

AU - Maslov, Leonid N.

AU - Lishmanov, Yury B.

AU - Oeltgen, Peter R.

AU - Barzakh, Eva I.

AU - Krylatov, Andrey V.

AU - Naryzhnaya, Natalia V.

AU - Pei, Jian Ming

AU - Brown, Stephen A.

PY - 2010/11

Y1 - 2010/11

N2 - Objectives: This study was conducted to test the hypothesis that opioid receptor (OR)-mediated cardioprotection is agonist specific when administered prior to coronary artery occlusion and reperfusion in a rat model. Methods: Anesthetized open-chest male Wistar rats were subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. Opioid agonists were infused 15 minutes prior to coronary artery occlusion. Two control groups and 15 opioid-treated groups were studied. Controls were infused with either saline alone (n = 16) or dimethyl sulfoxide plus hydroxypropyl-β-cyclodextrin in saline (n = 19). The μ-selective agonist DAMGO was infused at either 150 nmol/kg (n = 15) or 1500 nmol/kg (n = 14), and dermorphin-H was infused at 150 nmol/kg (n = 14). The δ1-selective agonist d-Pen2,5 enkephalin (DPDPE) was infused at 150 nmol/kg (n = 16) or 1500 nmol/kg (n = 14). The δ2-selective agonists deltorphin II (n = 16), deltorphin-Dvariant (n = 15), and deltorphin-E (n = 14) were infused at 150 nmol/kg. The selective κ1 opioid agonist U-50488 was infused at 240 nmol/kg (n = 14), 1500 nmol/kg (n = 14), and 2,400 nmol/kg (n = 14). The selective κ2 opioid agonist GR-89696 was infused at 150 nmol/kg (n = 14) and 1500 nmol/kg (n = 15). Orphinan FQ (nociceptin), also referred to as OR-like 1 (ORL1), was infused at 220 nmol/kg (n = 15) and 1500 nmol/kg (n = 15). The infarct size/area at risk (IS/AAR) ratio was determined after reperfusion by negative staining with patent blue violet dye. Hemodynamic parameters including heart rate, mean arterial blood pressure (MAP), and rate pressure product (RPP) were determined. Results: Pretreatment with the δ2 OR agonist deltorphin II (150 nmol/kg) significantly reduced the IS/AAR ratio, while deltorphin-Dvariant and deltorphin-E did not exhibit an infarct-sparing effect at that treatment dose. Activation of δ1 OR by DPDPE, κ1 OR by U-50488, κ2 OR by GR-89696, μ OR by DAMGO, dermorphin-H, and nociceptin had no effect on the IS/AAR ratio. U-50488 at 2,400 nmol/L induced a bradycardic effect. All other opioids had no effect on hemodynamic parameters at the doses tested. Conclusions: Peripheral δ2 OR activation by deltorphin II induces infarct size reduction in this animal model. Agonists of μ, δ1, κ1, κ2, and nociceptin receptors at the doses tested did not induce cardiac tolerance to ischemia/reperfusion injury in vivo.

AB - Objectives: This study was conducted to test the hypothesis that opioid receptor (OR)-mediated cardioprotection is agonist specific when administered prior to coronary artery occlusion and reperfusion in a rat model. Methods: Anesthetized open-chest male Wistar rats were subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. Opioid agonists were infused 15 minutes prior to coronary artery occlusion. Two control groups and 15 opioid-treated groups were studied. Controls were infused with either saline alone (n = 16) or dimethyl sulfoxide plus hydroxypropyl-β-cyclodextrin in saline (n = 19). The μ-selective agonist DAMGO was infused at either 150 nmol/kg (n = 15) or 1500 nmol/kg (n = 14), and dermorphin-H was infused at 150 nmol/kg (n = 14). The δ1-selective agonist d-Pen2,5 enkephalin (DPDPE) was infused at 150 nmol/kg (n = 16) or 1500 nmol/kg (n = 14). The δ2-selective agonists deltorphin II (n = 16), deltorphin-Dvariant (n = 15), and deltorphin-E (n = 14) were infused at 150 nmol/kg. The selective κ1 opioid agonist U-50488 was infused at 240 nmol/kg (n = 14), 1500 nmol/kg (n = 14), and 2,400 nmol/kg (n = 14). The selective κ2 opioid agonist GR-89696 was infused at 150 nmol/kg (n = 14) and 1500 nmol/kg (n = 15). Orphinan FQ (nociceptin), also referred to as OR-like 1 (ORL1), was infused at 220 nmol/kg (n = 15) and 1500 nmol/kg (n = 15). The infarct size/area at risk (IS/AAR) ratio was determined after reperfusion by negative staining with patent blue violet dye. Hemodynamic parameters including heart rate, mean arterial blood pressure (MAP), and rate pressure product (RPP) were determined. Results: Pretreatment with the δ2 OR agonist deltorphin II (150 nmol/kg) significantly reduced the IS/AAR ratio, while deltorphin-Dvariant and deltorphin-E did not exhibit an infarct-sparing effect at that treatment dose. Activation of δ1 OR by DPDPE, κ1 OR by U-50488, κ2 OR by GR-89696, μ OR by DAMGO, dermorphin-H, and nociceptin had no effect on the IS/AAR ratio. U-50488 at 2,400 nmol/L induced a bradycardic effect. All other opioids had no effect on hemodynamic parameters at the doses tested. Conclusions: Peripheral δ2 OR activation by deltorphin II induces infarct size reduction in this animal model. Agonists of μ, δ1, κ1, κ2, and nociceptin receptors at the doses tested did not induce cardiac tolerance to ischemia/reperfusion injury in vivo.

KW - heart

KW - ischemia

KW - opioid receptors

KW - reperfusion

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