Acute aspirin treatment abolishes, whereas acute ibuprofen treatment enhances morphine-induced cardioprotection: role of 12-lipoxygenase.
Patients suffering an acute myocardial infarction routinely receive morphine and nonsteroidal anti-inflammatory drugs (NSAIDs) alone or in combination. However, the importance of the dose, timing, or the combined administration of both on infarct size reduction has not been assessed. Additionally, it is not known whether morphine or NSAIDs require 12-lipoxygenase (12-LO) to mediate infarct size reduction as found previously for ischemic preconditioning. Male Sprague-Dawley rats were subjected to 30 min of ischemia and 2 h of reperfusion, followed by infarct size assessment (mean +/- S.E.M.%, **P < 0.01). Morphine (0.3 mg/kg), ibuprofen (3 mg/kg), but not aspirin (3 mg/kg) reduced infarct size when administered 5 min before reperfusion compared with vehicle (42.3 +/- 1.5**, 40.8 +/- 2.8**, 60.7 +/- 2.3 versus 59.1 +/- 1.7%, respectively); however, none of these agents reduced infarct size when administered 10 s after reperfusion. Ibuprofen (3 mg/kg) administered with morphine (0.3 mg/kg) reduced infarct size (43.7 +/- 1.3%**), whereas aspirin (1 and 3 mg/kg) abolished morphine-induced infarct size reduction. Morphine (0.2 mg/kg) and ibuprofen (0.6 mg/kg) given at doses not effective individually reduced infarct size when given together (59.0 +/- 1.4, 57.6 +/- 2.8, and 43.9 +/- 1.6%**, respectively). Morphine- and ibuprofen-induced infarct size reduction was abolished by the 12-LO inhibitor baicalein (3 mg/kg) and mimicked by the 12-LO metabolite 12-(S)-hydroxyeicosa-5Z,8Z,10Z,14Z-tetraenoic acid (45.2 +/- 2.5%**). These data suggest that morphine and ibuprofen reduce infarct size individually or at subthreshold doses in combination by 12-LO when administered 5 min before reperfusion. Furthermore, acute aspirin administration has a detrimental interaction with morphine that abrogates morphine-induced infarct size reduction.
Gross
Eric R
ER
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. ggross@mcw.edu
Hsu
Anna K
AK
Gross
Garrett J
GJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology*; D001241:Aspirin / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D004347:Drug Interactions; D004357:Drug Synergism; D006339:Heart Rate / Q000187:drug effects; D007052:Ibuprofen / Q000627:therapeutic use*; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications; D015425:Myocardial Reperfusion; D051381:Rats; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002316:Cardiotonic Agents; D009020:Morphine; D001092:Arachidonate 12-Lipoxygenase; D001241:Aspirin; D007052:Ibuprofen