title: Comparative hemodynamic effects of levosimendan alone and in conjunction with 4-aminopyridine or calcium chloride in a rodent model of severe verapamil poisoning.
abstract: Levosimendan (Levo) increases sensitivity of troponin-C to calcium, thus increasing myocardial contractility. It is also a vascular K+-ATP channel agonist producing peripheral vasodilation. Previous research with levosimendan revealed an increase in cardiac output (CO) but not blood pressure (BP) in experimental verapamil poisoning. Levosimendan's K+-channel agonist properties may augment verapamil's vasodilatory effects. 4-Aminopyridine (4-AP) is a K+-channel antagonist. It has successfully reversed hypotension in experimental verapamil poisoning. We hypothesized that coadministration of these agents may improve BP and CO in verapamil poisoning. Anesthetized, ventilated, and canulated male Wistar rats were poisoned with verapamil. Animals received one of six treatments, which are as follows: (1) n-saline infusion (control), (2) Levo 6.25 μg/kg loading dose and 36 μg/kg/h infusion, (3) 4-AP 2 mg/kg loading dose and infusion (4-AP), (4) Levo+4-AP, (5) CaCl₂ loading dose and infusion, and (6) Levo+CaCl(2). Hemodynamic parameters were recorded for 60 min. Outcome measures were changes in CO, BP, and heart rate (HR) compared to control. All groups had similar pretoxicity and peak toxicity CO (50% of pretoxicity value), BP (50% or pretoxicity value), and HR. Control group CO, BP, and HR progressively dropped during the verapamil infusion. Levosimendan produced a statistically significant improvement in CO (75% of pretoxicity level) but not BP in comparison to control. 4-AP produced a significant improvement in CO (110% of pretoxicity) and BP (78% of pretoxicity). Levo+4-AP and Levo+CaCl₂ groups improved CO (100% of pretoxicity) and BP (77% and 50% of pretoxicity, respectively), but there was no additive increase in CO or BP in animals compared to 4-AP or CaCl₂ alone. Levosimendan moderately improved CO but not BP in verapamil poisoning. The hypotensive effects of levosimendan were not overcome by coadministration of either 4-AP or CaCl₂. Levosimendan may not be an appropriate agent to use in the treatment of verapamil poisoning.
authors.affiliation: Clinical and Experimental Toxicology Unit, Department of Emergency Medicine, Prince of Wales Hospital, Randwick, NSW, Australia. andis.graudins@monash.edu
authors.forename: Andis
authors.initials: A
authors.lastname: Graudins
authors.forename: Kathy Ka Ling
authors.initials: KK
authors.lastname: Wong
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000506:poisoning*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006835:Hydrazones / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000077464:Simendan; D013534:Survival; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014700:Verapamil / Q000506:poisoning*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D006835:Hydrazones; D026902:Potassium Channel Blockers; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D015761:4-Aminopyridine; D014700:Verapamil; D002122:Calcium Chloride
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