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Cyclooxygenase-2 mediates ischemic, anesthetic, and pharmacologic preconditioning in vivo. Anesthesiology 2004 Mar;100(3):547-54

Date

04/28/2004

Pubmed ID

15108967

DOI

10.1097/00000542-200403000-00013

Abstract

BACKGROUND: Cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (IPC), but whether this enzyme modulates early IPC, anesthetic-induced preconditioning (APC), or other forms of pharmacologic preconditioning (PPC) is unknown. The authors tested the hypothesis that COX-2 is an essential mediator of IPC, APC, and PPC in vivo.

METHODS: Barbiturate-anesthetized dogs (n = 91) were instrumented for measurement of hemodynamics and randomly assigned to receive IPC (four 5-min coronary occlusions interspersed with 5-min reperfusions), APC (1.0 minimum alveolar concentration of isoflurane for 30 min), or PPC (selective mitochondrial K(ATP) channel opener diazoxide, 2.5 mg/kg intravenous) in the presence or absence of pretreatment with oral aspirin (650 mg), the selective COX-2 inhibitor celecoxib (200 mg), or acetaminophen (500 mg) administered 24, 12, and 2 h before experimentation in 12 separate experimental groups. All dogs were subjected to a 60-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were quantified with triphenyltetrazolium staining and radioactive microspheres, respectively. Myocardial 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, was measured (enzyme immunoassay) in separate experiments (n = 8) before and after isoflurane administration, in the presence or absence of celecoxib.

RESULTS: No significant differences in baseline hemodynamics or the left ventricular area at risk for infarction were observed between groups. IPC, isoflurane, and diazoxide all decreased myocardial infarct size (9 +/- 1, 12 +/- 2, and 11 +/- 1%, respectively) as compared with control (30 +/- 1%). Celecoxib alone had no effect on infarct size (26 +/- 3%) but abolished IPC (30 +/-3%), APC (30 +/- 3%), and PPC (26 +/- 1%). Aspirin (24 +/- 3%) and acetaminophen alone (29 +/- 2%) did not alter infarct size or abolish APC-induced protection (18 +/- 1 and 19 +/- 1%, respectively). Isoflurane increased myocardial 6-keto-prostaglandin F1alpha to 463 +/- 267% of baseline in the absence but not in the presence (94 +/- 13%) of celecoxib.

CONCLUSIONS: The results indicate that COX-2 is a critical mediator of IPC, APC, and PPC in dogs. The role of cyclooxygenase enzymes as obligatory mediators of myocardial protection produced by diverse preconditioning stimuli may have implications for the clinical use of COX-2 inhibitors.

Author List

Alcindor D, Krolikowski JG, Pagel PS, Warltier DC, Kersten JR

Author

Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

6-Ketoprostaglandin F1 alpha
Acetaminophen
Anesthetics, Inhalation
Animals
Aspirin
Celecoxib
Coronary Circulation
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Diazoxide
Dogs
Hemodynamics
Ischemic Preconditioning, Myocardial
Isoenzymes
Isoflurane
Membrane Proteins
Myocardial Infarction
Myocardium
Potassium Channels
Prostaglandin-Endoperoxide Synthases
Pyrazoles
Sulfonamides
jenkins-FCD Prod-409 d1e206b0be345926047b0d9c353c78a4cce4058b