title: Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation.
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.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, California, USA.
authors.forename: Mathivadhani
authors.initials: M
authors.lastname: Panneerselvam
authors.forename: Yasuo M
authors.initials: YM
authors.lastname: Tsutsumi
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bonds
authors.forename: Yousuke T
authors.initials: YT
authors.lastname: Horikawa
authors.forename: Michelle
authors.initials: M
authors.lastname: Saldana
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D000818:Animals; D002099:Cacao; D002392:Catechin / Q000494:pharmacology / Q000627:therapeutic use*; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
chemical_list: D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D011956:Receptors, Cell Surface; D017465:Receptors, Opioid, delta; D009270:Naloxone; D009271:Naltrexone; C052853:5-hydroxydecanoic acid; D002392:Catechin; C055382:naltrindole