Presented at the Southeastern Regional Society for Academic Emergency Medicine meeting, Wilmington, NC, 2007; and the National Society for Academic Emergency Medicine meeting, Chicago, IL, 2007.
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Verapamil Toxicity Dysregulates the Phosphatidylinositol 3-Kinase Pathway
Article first published online: 27 MAR 2008
DOI: 10.1111/j.1553-2712.2008.00088.x
© 2008 by the Society for Academic Emergency Medicine
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How to Cite
Bechtel, L. K., Haverstick, D. M. and Holstege, C. P. (2008), Verapamil Toxicity Dysregulates the Phosphatidylinositol 3-Kinase Pathway. Academic Emergency Medicine, 15: 368–374. doi: 10.1111/j.1553-2712.2008.00088.x
These studies were supported by a grant from the University of Virginia Department of Emergency Medicine Research Fund.
Publication History
- Issue published online: 27 MAR 2008
- Article first published online: 27 MAR 2008
- Received October 2, 2007; revisions received December 17 and December 19, 2007; accepted December 29, 2007.
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Keywords:
- calcium channel blockers;
- verapamil;
- high-dose insulin therapy;
- phosphatidylinositol 3-kinase;
- Akt;
- glucose transporter protein
Abstract
Objectives: Recent animal research and clinical case reports suggest benefit from high-dose insulin therapy (HDIT) for the treatment of calcium channel blocker (CCB) toxicity. One molecular signaling pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, that contributes to CCB toxicity and the efficacy of HDIT, was examined for a role in this phenomenon.
Methods: A differentiated 3T3-L1 adipocyte model system was utilized to characterize metabolic and molecular signaling events dysregulated in response to acute CCB toxicity. Glucose uptake assays were performed in the presence of representatives of three classes of CCB drugs, and the ability of HDIT to reverse observed inhibition was assessed. Western blot analyses were utilized to probe which insulin-dependent signaling pathway was inhibited by CCB toxicity.
Results: Representative compounds from the dihydropyridine and phenylalkylamine classes of CCBs were more effective at inhibiting glucose uptake in differentiated 3T3-L1 adipocytes than a representative from the benzothiazepine class. Phosphorylation at serine 473 of the Akt protein (P-Akt), a protein representing a common pathway for insulin receptors (IR), insulinlike growth factor receptors (IGFR), and hybrid receptors formed by IR and IGFR subunits, was abolished in the presence of toxic doses of the phenylalkylamine CCB verapamil. Phosphorylation at serine 473 of Akt was rescued in the presence high concentrations of insulin.
Conclusions: These data suggest that dysregulation of the insulin-dependent PI3K pathway is partially responsible for insulin resistance and the hyperglycemic state observed in response to acute CCB toxicity.