Acute toxicity of tedisamil, a new potassium channel blocking drug.
The acute intravenous toxicity of tedisamil, a new potassium channel blocker, was assessed by infusing it at various rates (1.5 to 10 mg/kg/min.) to ventilated or spontaneously breathing rats subjected to blockade of their peripheral somatic and autonomic nervous systems. The lethal doses for ventilated rats (including pithed animals) were 2-3 times higher than those for spontaneously breathing animals. In spontaneously breathing rats death appeared to be due to respiratory depression which was possibly of central origin since the lethality of tedisamil was not markedly altered by vagotomy, bilateral carotid artery ligation, nor by autonomic nervous system blockade. On the other hand, in all of the artificially ventilated groups, death occurred at higher doses and was related to direct cardiac actions, possibly involving blockade of cardiac potassium and sodium channels. The cardiovascular responses to infusions of tedisamil included tachyarrhythmias, bradycardia, blood pressure changes, increased QRS width and Q-T interval duration. Arrhythmias occurred at sublethal doses and were eliminated by autonomic blockade and pithing. However, the bradycardia, ECG and blood pressure changes induced by tedisamil infusions were unaltered by the various treatments. Thus tedisamil may induce arrhythmias by actions on the autonomic system.
Hayes
E
E
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Courtice
I D
ID
Abraham
S
S
Walker
M J
MJ
D000818:Animals; D001784:Blood Gas Analysis; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000633:toxicity*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002319:Cardiovascular System / Q000187:drug effects; D003521:Cyclopropanes / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D004562:Electrocardiography; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D026902:Potassium Channel Blockers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002316:Cardiotonic Agents; D003521:Cyclopropanes; D026902:Potassium Channel Blockers; C059921:tedisamil