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Monophosphoryl lipid A attenuates myocardial stunning in dogs: role of ATP-sensitive potassium channels.

Abstract
Results of previous studies indicate that monophosphoryl lipid A (MLA) reduces myocardial infarct size when administered 24 but not 1 h before a prolonged period of regional ischemia in dogs and rabbits. This cardioprotective effect of MLA could be reversed by the administration of the adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) blockers, glibenclamide, or 5-hydroxydecanoate. MLA also was shown to attenuate myocardial stunning in dogs; however, its mechanism in this model remains unknown. Therefore the major aim of our study was to determine the dose-related effect of MLA to enhance contractile function in stunned myocardium and to determine the role of the K(ATP) channel in mediating its cardioprotective effect. To produce myocardial stunning, barbital-anesthetized dogs were subjected to five cycles of 5 min of left anterior descending (LAD) coronary artery occlusion interspersed with 10 min of reperfusion and finally followed by 2 h of reperfusion. Regional segment shortening (%SS) was determined by sonomicrometers implanted in the subendocardium of the ischemic region. Single intravenous doses of MLA in the range of 10-35 microg/kg given 24 h before ischemia resulted in an improvement in %SS over a 2-h reperfusion period. Similar to results obtained in the canine and rabbit infarct models, cardioprotection against stunning with MLA appears to require activation of K(ATP) channels during ischemia, because glibenclamide (50 microg/kg, 15 min before ischemia) completely blocked the effect of MLA to improve regional %SS during reperfusion. Cardioprotective doses of MLA were without effect on systemic hemodynamics, blood gases, and pH throughout the experiment. No treatment-related effects on regional myocardial blood flow were observed during ischemia or reperfusion. These results suggest that MLA improves %SS at doses of 10-35 microg/kg by an ATP-sensitive potassium channel-dependent process, and that MLA may mimic the antistunning effects observed during the second window of ischemic preconditioning.
AuthorsG T Elliott, D A Mei, G J Gross
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 32 Issue 1 Pg. 49-56 (Jul 1998) ISSN: 0160-2446 [Print] United States
PMID9676720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Decanoic Acids
  • Hydroxy Acids
  • Hypoglycemic Agents
  • Lipid A
  • Potassium Channel Blockers
  • Potassium Channels
  • 5-hydroxydecanoic acid
  • Adenosine Triphosphate
  • monophosphoryl lipid A
  • Glyburide
Topics
  • Adenosine Triphosphate (physiology)
  • Animals
  • Blood Gas Analysis
  • Blood Pressure (drug effects)
  • Coronary Circulation (drug effects)
  • Decanoic Acids (pharmacology)
  • Dogs
  • Female
  • Glyburide (pharmacology)
  • Heart Rate (drug effects)
  • Hydrogen-Ion Concentration
  • Hydroxy Acids (pharmacology)
  • Hypoglycemic Agents (pharmacology)
  • Lipid A (analogs & derivatives, therapeutic use)
  • Male
  • Myocardial Contraction (drug effects)
  • Myocardial Reperfusion Injury (physiopathology)
  • Myocardial Stunning (drug therapy, physiopathology)
  • Potassium Channel Blockers
  • Potassium Channels (physiology)
  • Ventricular Function, Left (drug effects)

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