TAN-67, a delta 1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels.
We have previously shown that delta (delta)-opioid receptors, most notably delta 1, are involved in the cardioprotective effect of ischemic preconditioning (PC) in rats; however, the mechanism by which delta-opioid receptor-induced cardioprotection is mediated remains unknown. Therefore, we hypothesized that several of the known mediators of ischemic PC such as the ATP-sensitive potassium (KATP) channel and Gi/o proteins are involved in the cardioprotective effect produced by delta 1-opioid receptor activation. To address these possibilities, anesthetized, open-chest Wistar rats were randomly assigned to five groups. Control animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. To demonstrate that stimulating delta 1-opioid receptors produces cardioprotection, TAN-67, a new selective delta 1-agonist, was infused for 15 min before the long occlusion and reperfusion periods. In addition, one group received 7-benzylidenenaltrexone (BNTX), a selective delta 1-antagonist, before TAN-67. To study the involvement of KATP channels or Gi/o proteins in delta 1-opioid receptor-induced cardioprotection, glibenclamide (Glib), a KATP channel antagonist, or pertussis toxin (PTX), an inhibitor of Gi/o proteins, was administered before TAN-67. Infarct size (IS) as a percentage of the area at risk (IS/AAR) was determined by tetrazolium stain. TAN-67 significantly reduced IS/AAR as compared with control (56 +/- 2 to 27 +/- 5%, n = 5, P < 0.05). The cardioprotective effect of TAN-67 was completely abolished by BNTX, Glib, and PTX (51 +/- 3, 53 +/- 5, and 61 +/- 4%, n = 6 for each group, respectively). These results are the first to suggest that stimulating the delta 1-opioid receptor elicits a cardioprotective effect that is mediated via Gi/o proteins and KATP channels in the intact rat heart.
Schultz J el-J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Hsu
A K
AK
Nagase
H
H
Gross
G J
GJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000502:physiology*; D006339:Heart Rate; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology*; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001786:Blood Glucose; D015221:Potassium Channels; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go