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

objectivesThis 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.

methodsAnesthetized 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-D(variant) (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.

resultsPretreatment with the δ₂ OR agonist deltorphin II (150 nmol/kg) significantly reduced the IS/AAR ratio, while deltorphin-D(variant) 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.

conclusionsPeripheral 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.