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


OBJECTIVE
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 = 30 min (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.
Graudins
Andis
A
Clinical and Experimental Toxicology Unit and Department of Emergency Medicine, Prince of Wales Hospital, Randwick, Australia. andis.graudins@unsw.edu.au
Najafi
Javad
J
Rur-SC
Michael Perry M
MP
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002122:Calcium Chloride / Q000627:therapeutic use; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006835:Hydrazones / Q000627:therapeutic use*; D054086:KATP Channels / Q000819:agonists; D008297:Male; D011041:Poisoning / Q000188:drug therapy; D011724:Pyridazines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D000077464:Simendan; D015996:Survival Rate; D014665:Vasodilator Agents / Q000506:poisoning*; D014700:Verapamil / Q000506:poisoning*
D000931:Antidotes; D006835:Hydrazones; D054086:KATP Channels; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D014700:Verapamil; D002122:Calcium Chloride