Dependence of delta1-opioid receptor-induced cardioprotection on a tyrosine kinase-dependent but not a Src-dependent pathway.
We investigated the possibility that opioids activate a tyrosine kinase (TK) that mediates cardioprotection in an in vivo rat model of myocardial infarction. All animals underwent 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk (IS/AAR). Control animals had an IS/AAR of 58.2 +/- 0.6. Cardioprotection was induced with the delta1- or delta1/delta2-selective opioid agonists, TAN-67, or D-Ala D-Leu enkephalin (DADLE). Both significantly reduced IS/AAR (28.8 +/- 3.6 and 34.8 +/- 3.8, respectively). The general TK inhibitor, genistein, abolished cardioprotection produced by TAN-67 or DADLE (59.1 +/- 3.2 and 61.5 +/- 3.4, respectively), whereas the structural analog, daidzein, lacking TK inhibitory activity, did not. Interestingly, the selective Src/epidermal growth factor (EGF) receptor TK inhibitor, lavendustin A, did not abolish TAN-67-induced cardioprotection (22.1 +/- 6.8). Similarly, the Src-selective TK antagonist, PP2, had no effect on DADLE-induced cardioprotection (31.1 +/- 7.3). These unexpected findings suggest that Src and EGF receptor TKs are not important in the genesis of cardioprotection produced by TAN-67. Finally, we demonstrate that genistein did not affect protein kinase C (PKC) translocation induced by TAN-67. These data suggest that a TK, but most likely not an Src/EGF receptor TK, is important in cardioprotection via opioid receptor stimulation and that the pathway for TK activation is downstream from or parallel to PKC activation in the in situ rat heart since genistein could not affect PKC translocation of selective isoforms induced by TAN-67 and assessed by immunohistochemistry.
Fryer
R M
RM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Wang
Y
Y
Hsu
A K
AK
Nagase
H
H
Gross
G J
GJ
D000818:Animals; D005455:Fluorescent Antibody Technique; D016391:Genes, src / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology*; D014178:Translocation, Genetic / Q000235:genetics
D007527:Isoenzymes; D017465:Receptors, Opioid, delta; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C