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Effects of protein kinase C inhibitors in in situ and isolated ischemic rabbit myocardium.

Abstract
We tested the effects of the protein kinase C (PKC) inhibitors bisindolylmaleimide (1 microM) and chelerythrine (2 microM) on myocardial ischemia-reperfusion injury in in situ and isolated perfused rabbit hearts. In non-ischemic isolated hearts, bisindolylmaleimide (1 microM) and chelerythrine (2 microM) blocked sn-1,2-dioctanoylglycerol (DOG)-induced coronary vasoconstriction by approximately 80%. Intact hearts were subjected to 45 min coronary artery occlusion and 2 h reperfusion. Infarct size, determined by triphenyltetrazolium chloride (TTC)-staining and expressed as percentage of risk area, was reduced approximately 50% by both bisindolylmaleimide (0.05 mg/kg, i.v.) and chelerythrine (0.1 mg/kg, i.v.) compared to vehicle treated controls. In contrast, a higher dose of chelerythrine (3.8 mg/kg, i.v.) did not significantly reduce infarct size. Isolated hearts were subjected to 45 min of global normothermic (37 degrees C) ischemia and 60 min reperfusion. Control hearts exhibited 45+/-2% recovery of pre-ischemic left ventricular developed pressure (LVDP) compared to bisindolylmaleimide- (73+/-7%) and chelerythrine-treated hearts (70+/-11%). Bisindolylmaleimide and cherythrine reduced infarct size from a control value of 24+/-4 to 8+/-2 and 9+/-3%, respectively. Preconditioning isolated hearts with 5 min ischemia and 10 min reperfusion prior to prolonged ischemia reduced infarct size to 10.4+/-2.3%, an effect which was blocked by chelerythrine (22.5+/-4.2% infarct size). These results suggest that although PKC may play a role in ischemic preconditioning, PKC inhibitors can be cardioprotective during prolonged ischemia.
AuthorsR D Lasley, M A Noble, R M Mentzer Jr
JournalJournal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 29 Issue 12 Pg. 3345-56 (Dec 1997) ISSN: 0022-2828 [Print] England
PMID9441840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
CopyrightCopyright 1997 Academic Press Limited.
Chemical References
  • Alkaloids
  • Benzophenanthridines
  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Phenanthridines
  • Purines
  • chelerythrine
  • Protein Kinase C
  • bisindolylmaleimide
Topics
  • Alkaloids
  • Animals
  • Benzophenanthridines
  • Enzyme Inhibitors (pharmacology)
  • Female
  • In Vitro Techniques
  • Indoles (pharmacology)
  • Ischemic Preconditioning, Myocardial
  • Male
  • Maleimides (pharmacology)
  • Myocardial Infarction (enzymology)
  • Myocardium (enzymology)
  • Phenanthridines (pharmacology)
  • Protein Kinase C (antagonists & inhibitors)
  • Purines (metabolism)
  • Rabbits

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