Verapamil Toxicity Dysregulates the Phosphatidylinositol 3‐Kinase Pathway

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 insulindependent 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.ACADEMIC EMERGENCY MEDICINE 2008; 15:368-374 ª

Verapamil Inhibits the Glucose Transport Activity of GLUT1

“…Previous studies demonstrate that verapamil inhibits glucose uptake in insulin-sensitive tissues such as adipocytes skeletal myocytes and cardiac myocytes [3,9,[26][27][28]. The mechanism of this inhibition is largely unknown, but a recent study in 3T3 adipocytes suggested that verapamil inhibits the phosphorylation and activation of Akt, a downstream mediator of the insulin-dependent PI3K signaling system [3].…”

“…A CCB-dependent inhibition of glucose uptake has been documented in adipocytes [3,26,27], striated muscle [28], cardiac, and neuronal cells [29]. The cells or tissues used in these studies expressed more than one type of GLUT, and thus, the inhibitory activity was typically attributed to an effect on the most abundant transporter (GLUT4 for the insulin-sensitive cells).…”

“…The effects of CCBs at toxic doses are largely ascribed to four mechanisms: (1) inhibition of calcium influx through L-type calcium channels, (2) inhibition of myocardial fast sodium channels, (3) inhibition of insulin release from pancreatic islet cells producing hypoinsulemia and hyperglycemia, and (4) inhibition of glucose uptake in peripheral tissues [3][4][5][6][7][8][9]. The CCB-induced decreased contractility can generate a shock state with an accompanying reduction in cell perfusion.…”

l-Carnitine Increases Survival in a Murine Model of Severe Verapamil Toxicity

“…7,22,23 This in part is used for the explanation as to why high-dose insulin euglycemia reverses verapamil's toxicity; it in essence provides a myocardial energy source that sustains cardiac contractility in a situation where cardiac starvation might otherwise occur. It is therefore possible that in our model of verapamil toxicity, IV carnitine shifts cardiac metabolism back to its preferential source of energy: free fatty acids.…”

“…5 However, unlike other cardiac stressors, calcium channel antagonists block the utilization of glucose by both inhibiting insulin release from the pancreas and inhibiting the stress-regulated entry of glucose into cells for energy consumption. 6,7 Consequently, cardiac myocytes are deprived of both free fatty acids and glucose as energy sources, leading to shock.…”