Activation of delta- and kappa-opioid receptors by opioid peptides protects cardiomyocytes via KATP channels.
To examine the receptor specificity and the mechanism of opioid peptide-induced protection, we examined freshly isolated adult rabbit cardiomyocytes subjected to simulated ischemia. Cell death as a function of time was assessed by trypan blue permeability. Dynorphin B (DynB) and Met5-enkephalin (ME) limitation of cell death (expressed as area under the curve) was sensitive to blockade by naltrindole (NTI, a delta-selective antagonist) and 5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan (GNTI dihydrochloride, a kappa-selective antagonist): 85.7 +/- 2.7 and 142.9 +/- 2.7 with DynB and DynB + NTI, respectively (P < 0.001), 94.1 +/- 4.2 and 164.5 +/- 7.3 with DynB and DynB + GNTI, respectively (P < 0.001), 111.9 +/- 7.0 and 192.1 +/- 6.4 with ME and ME + NTI, respectively (P < 0.001), and 120.2 +/- 4.3 and 170.0 +/- 3.3 with ME and ME + GNTI, respectively (P < 0.001). Blockade of ATP-sensitive K+ channels eliminated DynB- and ME-induced protection: 189.6 +/- 5.4 and 139.0 +/- 5.4 for control and ME, respectively (P < 0.001), and 210 +/- 5.9 and 195 +/- 6.1 for 5-HD and ME + 5-HD, respectively (P < 0.001); 136.0 +/- 5.7 and 63.4 +/- 5.4 for control and ME, respectively (P < 0.001), and 144.6 +/- 4.5 and 114.6 +/- 7.7 for HMR-1098 and ME + HMR-1098, respectively (P < 0.01); 189.6 +/- 5.4 and 139.0 +/- 5.4 for control and ME, respectively (P < 0.001), and 210 +/- 5.9 and 195 +/- 6.1 for 5-HD and ME + 5-HD, respectively (P < 0.001); and 136.0 +/- 5.7 and 63.4 +/- 5.4 for control and ME, respectively (P < 0.001), and 144.6 +/- 4.5 and 114.6 +/- 7.7 for HMR-1098 and ME + HMR-1098, respectively (P < 0.01). We conclude that opioid peptide-induced cardioprotection is mediated by delta- and kappa-receptors and involves sarcolemmal and mitochondrial ATP-sensitive K+ channels.
Research and Anesthesiology Services, Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97201, USA.
Zhiping
Z
Cao
Lijuan
L
Liu
Donna M
DM
Van Winkle
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology*; D004723:Endorphins / Q000494:pharmacology*; D004744:Enkephalin, Methionine / Q000494:pharmacology*; D006146:Guanidines; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009019:Morphinans; D017202:Myocardial Ischemia / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism
C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D001549:Benzamides; D002316:Cardiotonic Agents; D004723:Endorphins; D006146:Guanidines; D009019:Morphinans; D009292:Narcotic Antagonists; D015221:Potassium Channels; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D004744:Enkephalin, Methionine; D009271:Naltrexone; D004399:Dynorphins; C036200:rimorphin; D000255:Adenosine Triphosphate; C410297:HMR 1098; C055382:naltrindole