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Essential activation of PKC-delta in opioid-initiated cardioprotection.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2001 Mar; Vol. 280 (3), pp. H1346-53. - Publication Year :
- 2001
-
Abstract
- Stimulation of the delta(1)-opioid receptor confers cardioprotection to the ischemic myocardium. We examined the role of protein kinase C (PKC) after delta-opioid receptor stimulation with TAN-67 or D-Ala(2)-D-Leu(5)-enkephalin (DADLE) in a rat model of myocardial infarction induced by a 30-min coronary artery occlusion and 2-h reperfusion. Infarct size (IS) was determined by tetrazolium staining and expressed as a percentage of the area at risk (IS/AAR). Control animals, subjected to ischemia and reperfusion, had an IS/AAR of 59.9 +/- 1.8. DADLE and TAN-67 administered before ischemia significantly reduced IS/AAR (36.9 +/- 3.9 and 36.7 +/- 4.7, respectively). The delta(1)-selective opioid antagonist 7-benzylidenenaltrexone (BNTX) abolished TAN-67-induced cardioprotection (54.4 +/- 1.3). Treatment with the PKC antagonist chelerythrine completely abolished DADLE- (61.8 +/- 3.2) and TAN-67-induced cardioprotection (55.4 +/- 4.0). Similarly, the PKC antagonist GF 109203X completely abolished TAN-67-induced cardioprotection (54.6 +/- 6.6). Immunofluorescent staining with antibodies directed against specific PKC isoforms was performed in myocardial biopsies obtained after 15 min of treatment with saline, chelerythrine, BNTX, or TAN-67 and chelerythrine or BNTX in the presence of TAN-67. TAN-67 induced the translocation of PKC-alpha to the sarcolemma, PKC-beta(1) to the nucleus, PKC-delta to the mitochondria, and PKC-epsilon to the intercalated disk and mitochondria. PKC translocation was abolished by chelerythrine and BNTX in TAN-67-treated rats. To more closely examine the role of these isoforms in cardioprotection, we utilized the PKC-delta selective antagonist rottlerin. Rottlerin abolished opioid-induced cardioprotection (48.9 +/- 4.8) and PKC-delta translocation without affecting the translocation of PKC-alpha, -beta(1), or -epsilon. These results suggest that PKC-delta is a key second messenger in the cardioprotective effects of delta(1)-opioid receptor stimulation in rats.
- Subjects :
- Acetophenones pharmacology
Alkaloids
Analgesics pharmacology
Animals
Benzophenanthridines
Benzopyrans pharmacology
Benzylidene Compounds pharmacology
Enzyme Activation drug effects
Enzyme Inhibitors pharmacology
Heart Rate
Indoles pharmacology
Male
Maleimides pharmacology
Myocardial Infarction drug therapy
Myocardial Infarction metabolism
Myocardial Reperfusion Injury drug therapy
Myocardial Reperfusion Injury metabolism
Myocardium enzymology
Naltrexone pharmacology
Narcotic Antagonists pharmacology
Phenanthridines pharmacology
Protein Kinase C-delta
Quinolines pharmacology
Rats
Rats, Wistar
Receptors, Opioid, delta agonists
Receptors, Opioid, delta antagonists & inhibitors
Enkephalin, Leucine-2-Alanine pharmacology
Ischemic Preconditioning, Myocardial
Isoenzymes metabolism
Myocardial Ischemia drug therapy
Myocardial Ischemia metabolism
Naltrexone analogs & derivatives
Protein Kinase C metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6135
- Volume :
- 280
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 11179083
- Full Text :
- https://doi.org/10.1152/ajpheart.2001.280.3.H1346