Selective block of IKs plays a significant role in MAP triangulation induced by IKr block in isolated rabbit heart.
BACKGROUND
The role of IKr (rapidly-activating delayed rectifier K(+) current) block in triangulation of monophasic action potentials (MAP) and in development of torsade de pointes (TdP) arrhythmia is known. Combined IKr and IKs (slowly-activating delayed rectifier K(+) current) block has been demonstrated to promote TdP. The aim of this study was to describe a possible implication of IKs block in MAP triangulation.


METHODS
Four contact electrodes were placed on the epicardium of the left ventricle of Langendorff-perfused rabbit hearts to record monophasic action potentials (MAP), with an IKr blocker d,l-sotalol (3 to 100 microM, n=6) or a non-selective IKr blocker, quinidine (1 to 30 microM, n=6). Their effects were assessed with or without a specific IKs blocker chromanol 293B (20 microM, n=6), on MAP duration at 30, 60 and 90% of repolarization (APD30, 60 and 90, respectively) and MAP triangulation (APD90-APD30) at 1 and 0.2 Hz.


RESULTS
D,L-sotalol increased significantly APD90 and triangulation with reverse use-dependency for concentrations > or =10 microM. Quinidine markedly prolonged APD90 and triangulation with reverse use-dependency at concentrations > or =3 microM. Chromanol 293B alone had no effects on APD, but when combined with D,L-sotalol or quinidine (i) increased APD prolonging effects, (ii) lowered values of pro-arrhythmic concentrations, (iii) increased incidence and length of D,L-sotalol- or quinidine-induced Early Afterdepolarizations (EADs) and TdP. All these events were primarily due to an important slowing of final repolarization, i.e. a marked increased triangulation.


CONCLUSIONS
IKs, even of low amplitude in rabbits, plays a key role in ventricular repolarization. IKs is involved in prolonged MAP duration mainly by triangulation and subsequent increased drug arrhythmogenicity. Therefore drug affinity for IKs must be evaluated with IKr studies as part of preclinical drug cardiac safety assessment.
Guérard
N C
NC
Novartis Pharma Ag, Exploratory Development, Safety Pharmacology, Basel, Switzerland.
Traebert
M
M
Suter
W
W
Dumotier
B M
BM
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism; D066298:In Vitro Techniques; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D013015:Sotalol / Q000008:administration & dosage / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D013015:Sotalol; D011802:Quinidine