The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels.
Vanadate has been shown to inhibit tyrosine phosphatase, leading to an increased tyrosine phosphorylation state. The latter has been demonstrated to be involved in the signal transduction pathway of ischemic preconditioning, the most potent endogenous mechanism to limit myocardial infarct size. Furthermore, there is evidence that phosphatase inhibition may be cardioprotective when given late after the onset of ischemia, but the mechanism of protection is unknown. We tested the hypothesis that the organic vanadate compound bis(maltolato)oxovanadium (BMOV) limits myocardial infarct size by attenuating reperfusion injury and investigated the underlying mechanism. Myocardial infarction was produced in 112 anesthetized rats by a 60-min coronary artery occlusion, and infarct size was determined histochemically after 180 min of reperfusion. Intravenous infusion of BMOV in doses of 3.3, 7.5, and 15 mg/kg i.v. decreased infarct size dose-dependently from 70 +/- 2% of the area at risk in vehicle-treated rats down to 41 +/- 5% (P < 0.05 versus control), when administered before occlusion. Administration of the low dose just before reperfusion was ineffective, but administration of the higher doses was equally cardioprotective as compared with administration before occlusion. The cardioprotection by BMOV was abolished by the tyrosine kinase inhibitor genistein and by the ATP-sensitive potassium (K(+)(ATP)) channel blocker glibenclamide but was not affected by the ganglion blocker hexamethonium. We conclude that BMOV afforded significant cardioprotection principally by limiting reperfusion injury. The mode of action appears to be by opening of cardiac K(+)(ATP) channels via increased tyrosine phosphorylation.
|Keywords||Adenosine Triphosphate/metabolism, Animals, Blood Pressure/drug effects, Cardiotonic Agents/therapeutic use, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors/*therapeutic use, Heart Rate/drug effects, Male, Membrane Proteins/drug effects/*metabolism/physiology, Myocardial Infarction/prevention & control, Myocardial Reperfusion Injury/*prevention & control, Potassium Channels, Protein-Tyrosine-Phosphatase/*antagonists & inhibitors/metabolism, Pyrones/*therapeutic use, Rats, Rats, Wistar, Research Support, Non-U.S. Gov't, Time Factors, Tyrosine/metabolism, Vanadates/*therapeutic use|
|Persistent URL||dx.doi.org/10.1124/jpet.103.062547, hdl.handle.net/1765/13334|
Liem, D.A., Gho, C.C., Gho, B.C.G., Kazim, S., Manintveld, O.C., Verdouw, P.D., & Duncker, D.J.G.M.. (2004). The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels.. The Journal of Pharmacology and Experimental Therapeutics, 309(3), 1256–1262. doi:10.1124/jpet.103.062547