Flumazenil mimics whereas midazolam abolishes ischemic preconditioning in a rabbit heart model of ischemia-reperfusion.
BACKGROUND
The goal of the current study was to assess the effects of flumazenil, a benzodiazepine receptor antagonist, in limiting infarct size and in reducing hydroxyl free radical production.


METHODS
After intravenous salicylate (100 mg/kg) administration, rabbits were subjected to 40 min of regional myocardial ischemia and 2 h of reperfusion. In one group, flumazenil (0.05 mg/kg) and, in another, midazolam (0.05 mg/kg) was administered 15 min before 40 min of ischemia. Ischemic preconditioning (IP) was elicited by 5 min of ischemia followed by 10 min of reperfusion (before the 40-min ischemia period). In two other groups, midazolam was added to flumazenil and IP. Infarct size was determined using triphenyl tetrazolium chloride staining. The authors quantified the hydroxyl-mediated conversion of salicylate to its 2,3- and 2,5-dihydroxybenzoate derivatives during reperfusion by high-performance liquid chromatography coupled with electrochemical detection. Results are expressed as mean +/- SEM.


RESULTS
Flumazenil, like IP, significantly decreased infarct size (23 +/- 4 and 22 +/- 5%, respectively, vs. 57 +/- 6% in control group; P < 0.01). Midazolam inhibited the effects of flumazenil and IP. Flumazenil and IP significantly limited the increase in the normalized concentrations of 2,3- and 2,5-dihydroxybenzoic acids. With midazolam, however, the increase was comparable to that of the control group. 5-Hydroxydecanoate, a selective mitochondrial adenosine triphosphate-sensitive K channel blocker, given with flumazenil, abolished the protection obtained with the latter.


CONCLUSIONS
Flumazenil mimics preconditioning to decrease infarct size and hydroxyl radical production during reperfusion. Midazolam, however, abolishes these effects. Blockade of benzodiazepine receptors is upstream to the mitochondrial adenosine triphosphate-sensitive K channels in the preconditioning cascade.
Rivo
Julia
J
Department of Anesthesiology and Critical Care Medicine, Hadassah-Hebrew University Medical Center and the Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
Raphael
Jacob
J
Drenger
Benjamin
B
Berenshtein
Eduard
E
Chevion
Mordechai
M
Gozal
Yaacov
Y
D000818:Animals; D004195:Disease Models, Animal; D005442:Flumazenil / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008874:Midazolam / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D011817:Rabbits
D005442:Flumazenil; D008874:Midazolam