title: Roles of tyrosine kinase and protein kinase C in infarct size limitation by repetitive ischemic preconditioning in the rat.
abstract: In this study, we examined the possibility that infarct-size limitation by repetitive preconditioning (PC) is achieved by activation of both protein kinase C (PKC) and tyrosine kinase. In addition, we assessed whether such kinase activation is triggered by angiotensin II type 1 (AT1) and alpha1-adrenergic receptors and whether sarcolemmal and mitochondrial adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play roles as effectors of cardioprotection in the rat. Under pentobarbital anesthesia, myocardial infarction was induced by 20-min coronary occlusion and 3-h reperfusion in the rat. Infarct size was determined by tetrazolium and expressed as a percentage of area at risk (%IS/AR). PC with one cycle of 5-min ischemia/5-min reperfusion before 20-min ischemia significantly reduced %IS/AR from the control value of 49.4 +/- 2.0 to 35.4 +/- 2.8, and repetitive PC with two cycles of 5-min ischemia/5-min reperfusion further limited %IS/AR to 3.2 +/-0.9. Infarct-size limitation by single-cycle PC was completely abolished by a PKC inhibitor, staurosporine (100 microg/kg; %IS/ AR, 45.7 +/- 5.0). In contrast, the cardioprotection by repetitive PC was only partially blocked by staurosporine (%IS/AR, 19.8 +/- 2.4), another PKC inhibitor, polymyxin B (5 mg/kg; %IS/AR, 16.2 +/- 3.1), or a tyrosine kinase inhibitor, genistein (5 mg/kg; %IS/AR, 21.8 +/- 1.4). However, a combined injection of genistein and staurosporine additively inhibited protection of repetitive PC (%IS/AR, 36.4 +/- 1.7). Staurosporine, polymyxin B, or genistein alone did not modify %IS/AR in nonpreconditioned rat hearts. Infarct-size limitation by repetitive PC was not attenuated by pretreatment with a selective AT1-receptor blocker (CV11974, 10 mg/kg), prazosin (0.6 mg/kg; %IS/AR, 6.4 +/- 3.2 and 1.6 +/- 0.5, respectively). A selective blocker of mitochondrial K(ATP) channels, 5-hydroxydecanoate (3 mg/kg), completely abolished the cardioprotective effect (%IS/AR, 50.8 +/-3.5), but HMR1883 (3 mg/kg), a selective blocker of sarcolemmal K(ATP) channels, failed to inhibit the preconditioning effect (%IS/AR, 4.4 +/- 0.7). These findings suggest that repetition of PC provokes activation of both PKC and tyrosine kinase, leading to enhanced antiinfarct tolerance by opening of mitochondrial but not sarcolemmal K(ATP) channels. It is unlikely that activation of either AT1 or alpha1-adrenergic receptor alone is crucial to trigger preconditioning. Key Words: Tyrosine kinase-Genistein-Angiotensin II-alpha1-Adrenergic receptor-Sarcolemmal K(ATP) channel-Mitochondrial K(ATP) channel.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanno
authors.forename: A
authors.initials: A
authors.lastname: Tsuchida
authors.forename: Y
authors.initials: Y
authors.lastname: Nozawa
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: K
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D015221:Potassium Channels / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D015221:Potassium Channels; D011942:Receptors, Adrenergic, alpha; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019311:Staurosporine