Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins.
BACKGROUND
Isoflurane-induced myocardial protection during ischemia is mediated by adenosine triphosphate-regulated potassium (KATP) channels; however, the intracellular signal transduction cascade responsible for this process has been incompletely evaluated. The authors tested the hypothesis that isoflurane reduces myocardial infarct size through a Gi protein-mediated process.


METHODS
Forty-eight hours after pretreatment with vehicle (0.9% saline) or the Gi protein inhibitor pertussis toxin (10 microg/kg intravenously), barbiturate-anesthetized dogs (n = 43) were instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3-h reperfusion. In four separate groups, vehicle- or pertussis toxin-pretreated dogs were studied with or without administration of 1 minimum alveolar concentration isoflurane. In two additional groups, dogs received the direct KATP channel agonist nicorandil (100 microg/kg bolus and 10 microg x kg-1 x min-1 intravenous infusion) in the presence or absence of pertussis toxin pretreatment. Myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively.


RESULTS
Isoflurane significantly (P < 0.05) decreased infarct size to 7 +/- 2% of the area at risk compared with control experiments (26 +/- 2%). Pertussis toxin pretreatment alone had no effects on myocardial infarct size (31 +/- 4%) but blocked the beneficial effects of isoflurane (21 +/- 3%). Nicorandil decreased infarct size (11 +/- 2%), but, in contrast to isoflurane, this effect was independent of pertussis toxin pretreatment (11 +/- 1%).


CONCLUSIONS
Isoflurane reduces myocardial infarct size by a Gi protein-mediated mechanism in vivo.
Toller
W G
WG
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Kersten
J R
JR
Gross
E R
ER
Pagel
P S
PS
Warltier
D C
DC
D018685:Anesthetics, Inhalation / Q000627:therapeutic use*; D000818:Animals; D004285:Dogs; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007530:Isoflurane / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D020108:Nicorandil / Q000494:pharmacology; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D018685:Anesthetics, Inhalation; D015221:Potassium Channels; D014665:Vasodilator Agents; D010566:Virulence Factors, Bordetella; D020108:Nicorandil; D007530:Isoflurane; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins