Probing the contribution of IKs to canine ventricular repolarization: key role for beta-adrenergic receptor stimulation.
BACKGROUND
In large mammals and humans, the contribution of IKs to ventricular repolarization is still incompletely understood.


RESULTS
In vivo and cellular electrophysiological experiments were conducted to study IKs in canine ventricular repolarization. In conscious dogs, administration of the selective IKs blocker HMR 1556 (3, 10, or 30 mg/kg PO) caused substantial dose-dependent QT prolongations with broad-based T waves. In isolated ventricular myocytes under baseline conditions, however, IKs block (chromanols HMR 1556 and 293B) did not significantly prolong action potential duration (APD) at fast or slow steady-state pacing rates. This was because of the limited activation of IKs in the voltage and time domains of the AP, although at seconds-long depolarizations, the current was substantial. Isoproterenol increased and accelerated IKs activation to promote APD95 shortening. This shortening was importantly reversed by HMR 1556 and 293B. Quantitatively similar effects were obtained in ventricular-tissue preparations. Finally, when cellular repolarization was impaired by IKr block, IKs block exaggerated repolarization instability with further prolongation of APD.


CONCLUSIONS
Ventricular repolarization in conscious dogs is importantly dependent on IKs. IKs function becomes prominent during beta-adrenergic receptor stimulation, when it promotes AP shortening by increased activation, and during IKr block, when it limits repolarization instability by time-dependent activation. Unstimulated IKs does not contribute to cellular APD at baseline. These data highlight the importance of the synergism between an intact basal IKs and the sympathetic nervous system in vivo.
Volders
Paul G A
PG
Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, Netherlands. p.volders@cardio.azm.nl
Stengl
Milan
M
van Opstal
Jurren M
JM
Gerlach
Uwe
U
Spätjens
Roel L H M G
RL
Beekman
Jet D M
JD
Sipido
Karin R
KR
Vos
Marc A
MA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000813:Anilides; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D022062:Electrophysiologic Techniques, Cardiac; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D016276:Ventricular Function; D014851:Wakefulness
D000318:Adrenergic beta-Agonists; D000813:Anilides; D000889:Anti-Arrhythmia Agents; D002839:Chromans; C420023:HMR 1556; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; C000982:resorantel; C074334:almokalant; D007545:Isoproterenol