Dependence of delta(1)-opioid receptor-induced cardioprotection on a tyrosine kinase-dependent but not a Src-dependent pathway

Citation
Rm. Fryer et al., Dependence of delta(1)-opioid receptor-induced cardioprotection on a tyrosine kinase-dependent but not a Src-dependent pathway, J PHARM EXP, 299(2), 2001, pp. 477-482
Citations number
35
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
00223565 → ACNP
Volume
299
Issue
2
Year of publication
2001
Pages
477 - 482
Database
ISI
SICI code
0022-3565(200111)299:2<477:DODRCO>2.0.ZU;2-7
Abstract
We investigated the possibility that opioids activate a tyrosine kinase (TK ) that mediates cardioprotection in an in vivo rat model of myocardial infa rction. All animals underwent 30 min of regional ischemia and 2 h of reperf usion. Infarct size was expressed as a percentage of the area at risk (IS/A AR). Control animals had an IS/AAR of 58.2 +/- 0.6. Cardioprotection was in duced with the delta (1)- or delta (1)/delta (2)-selective opioid agonists, TAN-67, or D-Ala D-Leu enkephalin (DADLE). Both significantly reduced IS/A AR (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, daidz ein, 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 cardiopro tection (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 ki nase 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 cardioprotecti on via opioid receptor stimulation and that the pathway for TK activation i s downstream from or parallel to PKC activation in the in situ rat heart si nce genistein could not affect PKC translocation of selective isoforms indu ced by TAN-67 and assessed by immunohistochemistry.