Differential effects of anesthetics on mitochondrial K(ATP) channel activity and cardiomyocyte protection.
BACKGROUND
Mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels play a pivotal role in mediating cardiac preconditioning. The effects of intravenous anesthetics on this protective channel have not been investigated so far, but would be of importance with respect to experimental as well as clinical medicine.


METHODS
Live cell microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct reporter of mitoK(ATP) channel activity, in response to the direct and highly selective mitoK(ATP) channel opener diazoxide, or to diazoxide following exposure to various anesthetics commonly used in experimental and clinical medicine. A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to substantiate the effects of the anesthetics on mitoK(ATP) channels with respect to myocyte viability.


RESULTS
Diazoxide-induced mitoK(ATP) channel opening was significantly inhibited by the anesthetics R-ketamine, and the barbiturates thiopental and pentobarbital. Conversely, urethane, 2,2,2-trichloroethanol (main metabolite of alpha-chloralose and chloral hydrate), and the opioid fentanyl potentiated the channel-opening effect of diazoxide, which was abrogated by coadministration of chelerythrine, a specific protein kinase C inhibitor. S-ketamine, propofol, xylazine, midazolam, and etomidate did not affect mitoK(ATP) channel activity. The significance of these modulatory effects of the anesthetics on mitoK(ATP) channel activity was substantiated in a cellular model of simulated ischemia, where diazoxide-induced cell protection was mitigated by R-ketamine and the barbiturates, while urethane, 2,2,2-trichloroethanol, and fentanyl potentiated myocyte protection.


CONCLUSIONS
These results suggest distinctive actions of individual anesthetics on mitoK(ATP) channels and provide evidence that the choice of background anesthesia may play a role in cardiac protection in both experimental and clinical medicine.
Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland. Michael.zaugg@ifa.usz.ch
Michael
M
Zaugg
Eliana
E
Lucchinetti
Donat R
DR
Spahn
Thomas
T
Pasch
Carlos
C
Garcia
Marcus C
MC
Schaub
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D019610:Cytoprotection; D003981:Diazoxide / Q000494:pharmacology; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D020011:Protective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014520:Urethane / Q000494:pharmacology
D000777:Anesthetics; D015221:Potassium Channels; D020011:Protective Agents; D014520:Urethane; D005023:Ethylene Chlorohydrin; D000255:Adenosine Triphosphate; C005849:2,2,2-trichloroethanol; D011493:Protein Kinase C; D003981:Diazoxide; D005283:Fentanyl