Tedisamil in a chronic canine model of atrial flutter.
Tedisamil inhibits several cardiac potassium channels including Ito, Ikr, and the adenosine triphosphate (ATP)-sensitive potassium channel (I(KATP)), which may be important in the initiation and maintenance of atrial arrhythmias. We herein report the efficacy of tedisamil in terminating and protecting against the reinduction of atrial flutter (AFL) in a conscious canine model. Sustained AFL (> 15 min) was induced in eight of 10 mongrel dogs by programmed atrial stimulation (PAS) 2-41 days after producing a surgical barrier to conduction in the right atrium. At the time of surgery, an epicardial electrode was attached to the right atrial appendage for pacing and recording. Normal saline, 1 ml/kg, was infused after 15 min of AFL as placebo. Tedisamil (1.0 mg/kg) was given intravenously after 30 min of sustained AFL while recording surface ECGs and atrial electrograms. Conversion to sinus rhythm was achieved in 10 of 10 trials (eight dogs) in a mean time of 20.5 s (SD, +/- 11.8 s). Tedisamil had a negative chronotropic effect lasting > or =2 h and was protective against the reinduction of AFL. In five dogs, PAS was able to induce AFL in only two of seven trials 2 h after drug infusion. The corrected QT interval (QTc) was lengthened for the first 15 min after tedisamil administration (mean, +/- 39.3 ms; p < 0.05), but thereafter returned to baseline. The QRS interval was not altered by tedisamil. Saline alone, given after 15 min of sustained AFL, converted AFL in one of 11 trials (eight dogs) but did not alter the RR interval, QTc, or QRS interval compared with values measured during AFL. No significant adverse effects of tedisamil were observed. The results indicate that tedisamil is effective in interrupting and/or preventing reinduction of canine AFL, possibly by prolonging atrial refractoriness through inhibition of one or more potassium ion repolarizing currents in atrial muscle. Further studies are required to address the exact mechanism by which tedisamil exerts its antiarrhythmic effect.
Fischbach
P S
PS
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Johnston
P V
PV
Friedrichs
G S
GS
Lucchesi
B R
BR
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001282:Atrial Flutter / Q000188:drug therapy*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D002908:Chronic Disease; D003521:Cyclopropanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D008297:Male; D009248:Nadolol / Q000494:pharmacology; D026902:Potassium Channel Blockers
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D026902:Potassium Channel Blockers; D009248:Nadolol; D000255:Adenosine Triphosphate; C059921:tedisamil