Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion. Anesthesiology 2016 Feb;124(2):428-42
Date
12/10/2015Pubmed ID
26646023Pubmed Central ID
PMC4718826DOI
10.1097/ALN.0000000000000974Scopus ID
2-s2.0-84955752355 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
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-3β, 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-3β 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.
Author List
Fettiplace MR, Kowal K, Ripper R, Young A, Lis K, Rubinstein I, Bonini M, Minshall R, Weinberg GMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAnesthesia Recovery Period
Anesthetics, Local
Animals
Blotting, Western
Bupivacaine
Cardiotoxicity
Disease Models, Animal
Drug Synergism
Fat Emulsions, Intravenous
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Heart
In Vitro Techniques
Insulin
Myocardium
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Rats
Rats, Sprague-Dawley
Signal Transduction
