PMID- 26646023
OWN - NLM
STAT- MEDLINE
DCOM- 20160601
LR  - 20181113
IS  - 1528-1175 (Electronic)
IS  - 0003-3022 (Print)
IS  - 0003-3022 (Linking)
VI  - 124
IP  - 2
DP  - 2016 Feb
TI  - Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during 
      Recovery and Potentiation by Lipid Emulsion.
PG  - 428-42
LID - 10.1097/ALN.0000000000000974 [doi]
AB  - BACKGROUND: The impact of local anesthetics on the regulation of glucose 
      homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated 
      protein kinase (AMPK) is unclear but important because of the implications for 
      both local anesthetic toxicity and its reversal by IV lipid emulsion (ILE). 
      METHODS: Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by 
      nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart 
      and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 
      s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3beta, AMPK, 
      acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals 
      received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) 
      signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a 
      reversible Pi3K inhibitor. RESULTS: Bupivacaine cardiotoxicity rapidly 
      dephosphorylated Akt at S473 to 63 +/- 5% of baseline and phosphorylated AMPK to 
      151 +/- 19%. AMPK activation inhibited targets downstream of mammalian target of 
      rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 
      to 31 +/- 8% of baseline sensitized Akt signaling in hearts resulting in 
      hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3beta to 390 +/- 64% 
      and 293 +/- 50% of baseline, respectively. Glycogen accumulated to 142 +/- 7% of 
      baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine 
      cardiotoxicity, whereas pretreating with a reversible inhibitor delayed the onset 
      of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 +/- 23% and 167 
      +/- 10% of baseline, respectively, but did not interfere with AMPK or targets of 
      mammalian target of rapamycin complex 1. CONCLUSION: Glucose handling by Akt and 
      AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of 
      these pathways by ILE contributes to lipid resuscitation.
FAU - Fettiplace, Michael R
AU  - Fettiplace MR
AD  - From the Department of Anesthesiology (M.R.F., K.K., R.R., A.Y., K.L., R.M., 
      G.W.) and Department of Medicine (I.R., M.B.), and Neuroscience Program (M.R.F.), 
      University of Illinois at Chicago, Chicago, Illinois; and Research and 
      Development Service, Jesse Brown Veterans Affairs Medical Center (M.R.F., K.K., 
      R.R., A.Y., K.L., I.R., G.W.), Chicago, Illinois.
FAU - Kowal, Katarzyna
AU  - Kowal K
FAU - Ripper, Richard
AU  - Ripper R
FAU - Young, Alexandria
AU  - Young A
FAU - Lis, Kinga
AU  - Lis K
FAU - Rubinstein, Israel
AU  - Rubinstein I
FAU - Bonini, Marcelo
AU  - Bonini M
FAU - Minshall, Richard
AU  - Minshall R
FAU - Weinberg, Guy
AU  - Weinberg G
LA  - eng
GR  - I01 BX001514/BX/BLRD VA/United States
GR  - U01 NS083457/NS/NINDS NIH HHS/United States
GR  - VA999999/Intramural VA/United States
GR  - 1U01NS083457-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Anesthesiology
JT  - Anesthesiology
JID - 1300217
RN  - 0 (Anesthetics, Local)
RN  - 0 (Fat Emulsions, Intravenous)
RN  - 0 (Insulin)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - Y8335394RO (Bupivacaine)
SB  - IM
MH  - AMP-Activated Protein Kinases/drug effects/metabolism
MH  - Anesthesia Recovery Period
MH  - Anesthetics, Local/*toxicity
MH  - Animals
MH  - Blotting, Western
MH  - Bupivacaine/*toxicity
MH  - Cardiotoxicity/metabolism
MH  - Disease Models, Animal
MH  - Drug Synergism
MH  - Fat Emulsions, Intravenous/metabolism/*pharmacology
MH  - Glycogen Synthase Kinase 3/drug effects/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Heart/*drug effects
MH  - In Vitro Techniques
MH  - Insulin/*metabolism
MH  - Myocardium/metabolism
MH  - Phosphatidylinositol 3-Kinases/drug effects/metabolism
MH  - Proto-Oncogene Proteins c-akt/drug effects/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*drug effects
PMC - PMC4718826
MID - NIHMS737435
COIS- Conflicts of Interest: Dr. Weinberg was awarded a US patent related to lipid 
      resuscitation, is co-founder of ResQ Pharma, Inc with Dr. Rubinstein and 
      established the educational website, www.lipidrescue.org, an educational Web site 
      on lipid emulsion as treatment of drug overdose and toxicity. The other authors 
      declare no competing interests.
EDAT- 2015/12/10 06:00
MHDA- 2016/06/02 06:00
PMCR- 2017/02/01
CRDT- 2015/12/10 06:00
PHST- 2015/12/10 06:00 [entrez]
PHST- 2015/12/10 06:00 [pubmed]
PHST- 2016/06/02 06:00 [medline]
PHST- 2017/02/01 00:00 [pmc-release]
AID - 10.1097/ALN.0000000000000974 [doi]
PST - ppublish
SO  - Anesthesiology. 2016 Feb;124(2):428-42. doi: 10.1097/ALN.0000000000000974.