Differential effects of dofetilide, amiodarone, and class lc drugs on left and right atrial refractoriness and left atrial vulnerability in pigs.
OBJECTIVE
Antiarrhythmic drugs have been shown to prolong right atrial refractoriness while data on the left atrium are not available. In pigs we have observed shorter effective refractory periods (ERP) of the left compared with the right atrium associated with a much higher left atrial vulnerability for tachyarrhythmias. Since this could suggest a different distribution of repolarizing ion channels in left and right atrium, we investigated whether antiarrhythmic drugs blocking different ion channels have a differential effect on left and right atrial ERP and left atrial vulnerability.


METHODS
In pentobarbital-anesthetized pigs (n=40) we measured and compared ERPs in both atria before and after different drugs with the S1-S2 extrastimulus method at three basic cycle lengths (BCL) and assessed the inducibility of atrial fibrillation/flutter (AF/AFL) by the premature S2 stimulus.


RESULTS
At the three BCL tested (240/300/400 ms) baseline ERPs were shorter in left vs. right atrium (112+/-2/124+/-2/129+/-2 ms vs. 147+/-2/163+/-2/167+/-2 ms, P<0.001). Mostly non-sustained AF/AFL induced by the S2 extrastimulus was very frequent in the left (68%) and nearly absent in the right atrium (3%). Only amiodarone, 5 mg/kg i.v., which showed a balanced increase of left and right atrial ERP (29+/-5/33+/-4/35+/-3% vs. 30+/-5/35+/-5/42+/-7%), decreased the inducibility of AF/AFL significantly (-72%, P<0.01). Dofetilide, 10 microg/kg i.v., had a stronger effect on right than left atrial ERP (36+/-4/39+/-5/46+/-10% vs. 23+/-2/22+/-7/22+/-5%, P<0.05), while flecainide, 1 mg/kg i.v., prolonged left more than right atrial ERP (58+/-15/36+/-7/40+/-7% vs. 26+/-5/24+/-5/21+/-4%, P<0.05) similar to 1 mg/ kg of propafenone (46+/-5/45+/-7/32+/-10% vs. 17+/-4/21+/-5/ 25+/-8%, P<0.05).


CONCLUSIONS
The shorter refractoriness of the left compared with the right atrium observed in pigs was associated with a high left atrial vulnerability for tachyarrhythmias, which was reduced only by amiodarone showing a balanced increase of left and right atrial ERP. Dofetilide was stronger on right atrial ERP, flecainide and propafenone on left atrial ERP. These differences suggest a differential distribution of repolarizing ion channels between left and right atrium with possible relevance for the antiarrhythmic efficacy of drugs.
Wirth
K J
KJ
DG Cardiovascular Diseases, Aventis Pharma, Industriepark Höchst, Frankfurt am Main, Germany. klaus.wirth@aventis.com
Knobloch
K
K
D000638:Amiodarone / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy; D001282:Atrial Flutter / Q000188:drug therapy; D016279:Atrial Function, Left / Q000187:drug effects* / Q000502:physiology; D016280:Atrial Function, Right / Q000187:drug effects* / Q000502:physiology; D005424:Flecainide / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology* / Q000627:therapeutic use; D011405:Propafenone / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D011405:Propafenone; D005424:Flecainide; D000638:Amiodarone; C063533:dofetilide