Verapamil toxicity dysregulates the phosphatidylinositol 3-kinase pathway.
OBJECTIVE
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.
Bechtel
Laura K
LK
Division of Medical Toxicology, Department of Emergency Medicine, University of Virginia, Charlottesville, VA, USA. lkb2n@virginia.edu
Haverstick
Doris M
DM
Holstege
Christopher P
CP
D017667:Adipocytes / Q000378:metabolism*; D000730:Androstadienes / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000633:toxicity*; D002478:Cells, Cultured; D004110:Diltiazem / Q000633:toxicity; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D009543:Nifedipine / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014700:Verapamil / Q000633:toxicity*; D000077191:Wortmannin
D000730:Androstadienes; D002121:Calcium Channel Blockers; D007328:Insulin; D014700:Verapamil; D019869:Phosphatidylinositol 3-Kinases; D004110:Diltiazem; D009543:Nifedipine; D005947:Glucose; D000077191:Wortmannin