Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion

Karlsson, Lars; Grip, Lars; Bissessar, Erik; Bobrova, Irina; Gustafsson, Thomas; Kavianipour, Mohammad; Odenstedt, Jacob; Wikström, Gerhard; Gonon, Adrian

doi:10.1016/j.ejphar.2010.10.069

Cited by 14 publications

(13 citation statements)

References 29 publications

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“…This finding that a drug (EP 94) produces an effect 24 h later similar in magnitude to when the drug was administered acutely is unique. Interestingly, 1400W did not block the acute effect of EP 94 which is not surprising since eNOS is a more likely target for the early phase of protection [5]. Similar results have been previously reported by Fryer et al [13] and Jiang et al [14] in rats and mice where these investigators found that the selective δ 1 -opioid receptor agonist TAN-67 and morphine produced a second window of cardioprotection which was mediated by iNOS upregulation.…”

Section: Discussionsupporting

confidence: 80%

“…It is likely that EP 94 did not get to the heart during the ischemic period and its action probably occurs during the early reperfusion period. It would be of interest to determine if EP 94 is equally effective in rat hearts when administered just prior to reperfusion as suggested by recent data obtained in pig hearts [5], since this is the point where the heart is most susceptible to reperfusion-induced injury.…”

Section: Discussionmentioning

confidence: 99%

“…This is the first paper to demonstrate that opioids produce an increase of eNOS activity and NO release. Based on these intriguing results [5], and evidence that several NOS isoforms mediate cardioprotection [6–8], we extended these studies to determine the NOS isoforms that mediate the acute and chronic effects of EP 94 in a rat model of infarction. Our second objective was to determine the role of the sarc- and mito- K ATP channel in mediating the acute and chronic effect of EP 94 to reduce infarct size in the rat heart.…”

Section: Introductionmentioning

confidence: 99%

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Acute and Chronic Cardioprotection by the Enkephalin Analogue, Eribis Peptide 94, is Mediated via Activation of Nitric Oxide Synthase and Adenosine Triphosphate-Regulated Potassium Channels

et al. 2012

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Background/Aims: Eribis peptide 94 (EP 94) is a new enkephalin derivative which potently binds to the µ- and δ-opioid receptor. In this study, we determined the effects of EP 94 and potential mechanism(s) involved in cardioprotection of the rat heart. Methods and Results: An acute (5 and10 min into ischemia) and a chronic (24 h prior to ischemia) EP 94 administration produced a similar 30–40% reduction in infarct size/area at risk and the effects were blocked by the K_ATP channel antagonists, HMR 1098 and 5-HD. The cardioprotective effects were blocked by a nonselective nitric oxide synthase (NOS) inhibitor (L-NAME) following acute administration and by a selective iNOS inhibitor (1400W) following chronic administration. Conclusion: These results suggest that EP 94 may have potential for the treatment of ischemic heart disease via a nitric oxide (NO)-K_ATP-mediated mechanism.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute and Chronic Cardioprotection by the Enkephalin Analogue, Eribis Peptide 94, is Mediated via Activation of Nitric Oxide Synthase and Adenosine Triphosphate-Regulated Potassium Channels

et al. 2012

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“…In support of a cardioprotective role for EP 94, Karlsson et al 10 demonstrated in pigs that an intravenous dose of EP 94 reduced infarct size whether administered early or late during a 40 min ischemic period. They also found that EP 94 given intracoronary at 30 min of ischemia significantly reduced infarct size which suggested that EP 94 was having a direct myocardial effect to produce cardioprotection.…”

Section: Introductionmentioning

confidence: 99%

Eribis Peptide 94 Reduces Infarct Size in Rat Hearts Via Activation of Centrally Located μ Opioid Receptors

Gross¹,

Hsu²,

Nithipatikom³

et al. 2012

Journal of Cardiovascular Pharmacology

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Eribis peptide 94 (EP 94) is a novel enkephalin derivative which binds with high potency to μ and δ opioid receptors with less affinity for the κ opioid receptor. This compound has recently been shown to produce an acute reduction in myocardial infarct size in the anesthetized pig and rat partially via an eNOS- and KATP channel-dependent mechanism. EP 94 also was found to produce a chronic reduction in infarct size 24 hrs post drug administration via the upregulation of iNOS in rats. In spite of these findings, no data have emerged in which the opioid receptor subtype responsible for cardioprotection has been identified and the site of action, heart, other peripheral organs or the CNS have not been addressed. In the current study, EP 94, was administered in 2 divided doses (0.5 ug/kg, iv) at 5 and 10 min into the ischemic period and the opioid antagonists were administered 10 min prior to the onset of the 30 min ischemic period. The selective antagonists used were the μ receptor antagonist CTOP, the δ receptor antagonists, naltrindole and BNTX and the κ receptor antagonist, nor-BNI. Surprisingly, only CTOP completely blocked the cardioprotective effect of EP 94, whereas, naltrindole, BNTX and nor-BNI had modest but nonsignificant effects. Since there is controversial evidence suggesting that μ receptors may be absent in the adult rat myocardium, it was hypothesized that the protective effect of EP 94 may be mediated by an action outside the heart, perhaps in the CNS. To test this hypothesis, rats were pretreated with the nonselective opioid antagonist, naloxone HCl (NAL), which penetrates the blood brain barrier (BBB) or naloxone methiodide (NME), the quaternary salt of NAL, which does not penetrate the BBB prior to EP 94 administration. In support of a CNS site of action for EP 94, NAL completely blocked its cardioprotective effect, whereas, NME had no effect. These results suggest that EP 94 reduces IS/AAR in the rat primarily via activation of central μ opioid receptors.

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“…[11], [12] The pigs were bred in Swedish farms and brought to the animal laboratory one week prior to the ischemia and reperfusion procedure, where they were kept together until the intervention. The day before the procedure the pigs received 75 mg of acetic-salicylic acid (Trombyl, Pfizer, Sollentuna, Sweden).…”

Section: Methodsmentioning

confidence: 99%

Cholesteryl Esters Accumulate in the Heart in a Porcine Model of Ischemia and Reperfusion

et al. 2013

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Myocardial ischemia is associated with intracellular accumulation of lipids and increased depots of myocardial lipids are linked to decreased heart function. Despite investigations in cell culture and animal models, there is little data available on where in the heart the lipids accumulate after myocardial ischemia and which lipid species that accumulate. The aim of this study was to investigate derangements of lipid metabolism that are associated with myocardial ischemia in a porcine model of ischemia and reperfusion. The large pig heart enables the separation of the infarct area with irreversible injury from the area at risk with reversible injury and the unaffected control area. The surviving myocardium bordering the infarct is exposed to mild ischemia and is stressed, but remains viable. We found that cholesteryl esters accumulated in the infarct area as well as in the bordering myocardium. In addition, we found that expression of the low density lipoprotein receptor (LDLr) and the low density lipoprotein receptor-related protein 1 (LRP1) was up-regulated, suggesting that choleteryl ester uptake is mediated via these receptors. Furthermore, we found increased ceramide accumulation, inflammation and endoplasmatic reticulum (ER) stress in the infarcted area of the pig heart. In addition, we found increased levels of inflammation and ER stress in the myocardium bordering the infarct area. Our results indicate that lipid accumulation in the heart is one of the metabolic derangements remaining after ischemia, even in the myocardium bordering the infarct area. Normalizing lipid levels in the myocardium after ischemia would likely improve myocardial function and should therefore be considered as a target for treatment.

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Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion

Cited by 14 publications

References 29 publications

Acute and Chronic Cardioprotection by the Enkephalin Analogue, Eribis Peptide 94, is Mediated via Activation of Nitric Oxide Synthase and Adenosine Triphosphate-Regulated Potassium Channels

Acute and Chronic Cardioprotection by the Enkephalin Analogue, Eribis Peptide 94, is Mediated via Activation of Nitric Oxide Synthase and Adenosine Triphosphate-Regulated Potassium Channels

Eribis Peptide 94 Reduces Infarct Size in Rat Hearts Via Activation of Centrally Located μ Opioid Receptors

Cholesteryl Esters Accumulate in the Heart in a Porcine Model of Ischemia and Reperfusion

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