Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation

Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1604-9. doi: 10.1152/ajpheart.00073.2010. Epub 2010 Sep 10.

Abstract

Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH(2)-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to produce cardiac protection from ischemia-reperfusion injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cacao*
  • Catechin / pharmacology
  • Catechin / therapeutic use*
  • Decanoic Acids / pharmacology
  • Dose-Response Relationship, Drug
  • Hydroxy Acids / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / prevention & control*
  • Naloxone / pharmacology
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Potassium Channel Blockers / pharmacology
  • Receptors, Cell Surface / metabolism*
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, delta / metabolism*

Substances

  • Decanoic Acids
  • Hydroxy Acids
  • Potassium Channel Blockers
  • Receptors, Cell Surface
  • Receptors, Opioid, delta
  • Naloxone
  • Naltrexone
  • 5-hydroxydecanoic acid
  • Catechin
  • naltrindole