[Perspectives and limitations in the treatment of vagus-induced atrial fibrillation. Insights from cellular pharmacology].
OBJECTIVE
Pharmacological treatment of atrial fibrillation (AF) is limited by induction of malignant ventricular arrhythmias. Developing new drugs, a promising strategy is a more specific treatment of the atria. Muscarinic potassium current (IK[ACh]) is predominantly expressed in supraventricular tissue and mediates the induction of vagus-induced AF. The authors investigated the profile of representative class III drugs in respect to their effect on IK(ACh).


METHODS
In rat atrial myocytes, IK(ACh) was activated by acetylcholine (ACh) measured with the whole-cell voltage clamp method. Drugs used: selective IKs blocker chromanole 293B (Cro); IKr blockers sotalol (Sot), dofetilide (Dof), ibutilide (Ibu), and terikalant (Ter). Data are expressed as mean values +/- standard deviation (SD).


RESULTS
ACh-induced IK(ACh) density was 73 +/- 9 pA/pF (n= 9). IK(ACh) was almost completely desensitized in the presence of 50 micro M Ter, Ibu, or Dof. IC(50) of IK(ACh) inhibition by the three drugs was 0.9, 2.8, and 4.2 micro M (Dof, Ibu, and Ter, respectively). Receptor-independent GTP-gamma-S-induced IK(ACh) was sensitive to Ter, Ibu, and Dof as well. Sot is known to be a weak inhibitor of IKr. Inhibition of IK(ACh) by Sot was much less potent (IC(50) = 35.5 micro M) than inhibition by the high-affinity IKr blockers Ter, Ibu, and Dof. Superfusion of the cells with the IKs blocker Cro showed no desensitization of IK(ACh). Applied via the patch pipette (< 40 min) none of the class III drugs were effective.


CONCLUSIONS
The results indicate inhibition of IK(ACh) and IKr but not IKs to be of similar mechanism (direct ion channel inhibition from the external side of the membrane). Potent desensitization of muscarinic potassium current could be of clinical relevance especially in patients with vagus-induced AF.
Brandts
Bodo
B
Medizinische Klinik II (Schwerpunkte Kardiologie und Angiologie), Ruhr-Universität Bochum, Bochum. Bodo.Brandts@rub.de
Van Bracht
Marc
M
Dirkmann
Daniel
D
Borchard
Rolf
R
Wickenbrock
Ingo
I
Prull
Magnus Wilhelm
MW
Meine
Mathias
M
Trappe
Hans-Joachim
HJ
D000328:Adult; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D002478:Cells, Cultured; D003470:Culture Media; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013015:Sotalol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014630:Vagus Nerve / Q000502:physiology*
D000889:Anti-Arrhythmia Agents; D003470:Culture Media; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C067192:ibutilide; D013015:Sotalol; C063533:dofetilide