Treatment of experimental verapamil poisoning with levosimendan utilizing a rodent model of drug toxicity

Abstract

Background. Levosimendan is an inotropic agent used in the treatment of heart failure. It is a myocardial calcium sensitizer, binding to cardiac troponin-C, and a vascular K⁺_ATP-channel agonist producing peripheral vasodilatation. Aims. To assess the effect of levosimendan on cardiac output (CO), blood pressure (BP), and heart rate (HR) in a rodent model of severe verapamil poisoning. Methods. Male Wistar rats were anesthetized, ventilated, and canulated with jugular and femoral venous catheters and a femoral arterial catheter. CO, systolic BP, MAP, and HR were recorded. Verapamil was infused at 6 mg/kg/h until MAP dropped to 50% of baseline (time-0) and then reduced to 4 mg/kg/h. There were five treatment groups (n = 7 per group): 1) normal saline infusion (control); 2) CaCl₂ loading dose and infusion (CaCl₂); 3) levosimendan 24 microgram/kg loading dose and 0.6 microgram/kg/min infusion (Levo-24); 4) levosimendan 6 microgram/kg loading dose and 0.4 microgram/kg/min infusion (Levo-6); and 5) levosimendan 0.4 microgram/kg/min infusion with concurrent CaCl₂ loading dose and infusion (Levo + CaCl₂). Hemodynamic parameters were recorded for 70 minutes. Primary outcome measures were changes observed in CO, BP, and HR with treatments compared to control. Secondary outcome measure was survival. Results were analyzed using one-way ANOVA with Dunnet's post-test comparison with the control group. Results. All groups had similar BP, HR, and CO at base line and peak toxicity. The control group's HR, BP, and CO progressively fell during the verapamil infusion. Levo-24, Levo + CaCl₂, and CaCl₂ maintained CO compared with control from t = 20 min and Levo6 from t = 30min (p < 0.05). CaCl₂ (from t = 10 min) and Levo + CaCl₂ (from t = 20 min) produced significant improvements in BP compared to control. However, BP did not return to pre-toxicity levels. Levo-6 and Levo-24 groups did not recover from the hypotension seen at pre-treatment maximal toxicity. HR was maintained in all treatment groups compared to control animals. Twenty-nine percent (2/7) of control, 86% (6/7) levosimendan, 100% (7/7) CaCl₂, and Levo + CaCl₂ animals survived to the end of the protocol. Conclusions. Levosimendan increased CO in this model of verapamil poisoning to a similar degree as CaCl₂ alone, but it did not improve BP from time of maximal toxicity. The addition of CaCl₂ to Levosimendan did not appear to result in any further improvement in CO and BP compared to CaCl₂ alone. The failure of levosimendan to improve BP may result from vasodilation induced by levosimendan peripheral vascular K⁺_ATP-channel agonism. This may compound the vasodilatory effects of verapamil and offset any hemodynamic improvements produced by increased cardiac output.

Keywords:

• Verapamil
• Poisoning
• Levosimendan
• Antidote
• Animal model

Acknowledgments

This study was supported by a University of New South Wales Faculty of Medicine Research Grant. Levosimendan for this study was kindly donated by Abbott Australasia.

Notes

*Difference in mortality between CaCl₂ and LevoCaCl₂ and control group animals at 70 min was statistically significant (p = 0.02, Fisher's Exact Test).