Comparative Analysis of the Cardioprotective Properties of Opioid Receptor Agonists in a Rat Model of Myocardial Infarction

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-b-cyclodextrin in saline (n = 19). The l-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 d 1 -selective agonist D-Pen 2,5 enkephalin (DPDPE) was infused at 150 nmol ⁄ kg (n = 16) or 1500 nmol ⁄ kg (n = 14). The d 2 -selective agonists deltorphin II (n = 16), deltorphin-D variant (n = 15), and deltorphin-E (n = 14) were infused at 150 nmol ⁄ kg. The selective j 1 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 j 2 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 d 2 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 d 1 OR by DPDPE, j 1 OR by U-50488, j 2 OR by GR-89696, l 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 d 2 OR activation by deltorphin II induces infarct size reduction in this animal model. Agonists of l, d 1 , j 1 , j 2 , and nociceptin receptors at the doses tested did not induce cardiac tolerance to ischemia ⁄ reperfusion injury in vivo.

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

“…Selective μ-OR agonists, DAMGO and dermorphin H, had no effect on infarct size in naïve rats (Schultz et al, 1998;Maslov et al, 2010) and μ-OR antagonist failed to abolish the protective effect of preconditioning (Schultz et al, 1998). Ramifentanil, a short-acting μ-OR agonist, was shown to produce cardioprotection via activation of κ-and δ-ORs rather than μ-OR (Zhang et al, 2005).…”

Effect of Chronic Continuous Normobaric Hypoxia on Functional State of Cardiac Mitochondria and Tolerance of Isolated Rat Heart to Ischemia and Reperfusion: Role of µ and δ2 Opioid Receptors

“…Concerning the role of μ OR in cardioprotection, the data are contradictory. Some studies have been shown that selective μ agonists do not affect infarct size in vivo (Maslov et al 2010, Mukhomedzyanov et al 2016, Schultz et al 1998). On the other hand, the selective μ 2 OR agonist endomorphin-1 reduced myocardial infarction in another study (Zhang et al 2016).…”

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

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“…Many DOR1- and DOR2-subtype selective agonists (DPDPE (Charron et al 2008; Lasukova et al 2009; Yang et al 2011), SNC-121(Patel et al 2006), Eribis peptide 94(Karlsson et al 2011), fentanyl isothiocyanate[FIT] (Gross et al 2005), BW373U86 (Peart et al 2011), TAN-67 (Guo et al 2005), ARD-353 (Watson et al 2006), deltorphin II (Maslov et al 2010a) have cardioprotective abilities. While a study by Mslov et al suggested that only the DOR2 selective deltorphin II, but not DPDPE, reduced infarct size (Maslov et al 2010b), these differences may relate to experimental procedures (e.g. duration of occlusion, reperfusion).…”