Pharmacological blockade of IKs destabilizes spiral-wave reentry under β-adrenergic stimulation in favor of its early termination.
We tested a hypothesis that an enhancement of I(Ks) may play a pivotal role in ventricular proarrhythmia under high sympathetic activity. A 2-dimensional ventricular muscle layer was prepared in rabbit hearts, and action potential signals were analyzed by optical mapping. During constant stimulation, isoproterenol (ISP, 0.1 µM) significantly shortened action potential duration (APD); chromanol 293B (30 µM), a selective I(Ks)-blocker, reversed the APD shortening. VTs induced in the presence of ISP lasted longer than in the control, and this was reversed by 293B. E-4031 (0.1 µM), a selective I(Kr)-blocker, did not cause such reversal. Spiral-wave (SW) reentry with ISP was characterized by more stable rotation around a shorter functional block line (FBL) than in the control. After application of 293B, SW reentry was destabilized, and rotation around a longer FBL with prominent drift reappeared. The APD abbreviation by ISP close to the rotation center was more pronounced than in the periphery, leading to an opposite APD gradient (center < periphery) compared with controls. This effect was also reversed by 293B. In conclusion, β-adrenergic stimulation stabilizes SW reentry most likely though an enhancement of I(Ks). Blockade of I(Ks) may be a promising therapeutic modality in prevention of ventricular tachyarrhythmias under high sympathetic activity.
Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Japan.
Sara
S
Kato
Haruo
H
Honjo
Yoshio
Y
Takemoto
Hiroki
H
Takanari
Tomoyuki
T
Suzuki
Yusuke
Y
Okuno
Tobias
T
Opthof
Ichiro
I
Sakuma
Shin
S
Inada
Kazuo
K
Nakazawa
Takashi
T
Ashihara
Itsuo
I
Kodama
Kaichiro
K
Kamiya
D000200:Action Potentials / Q000187:drug effects; D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000517:prevention & control; D002839:Chromans / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism
D018663:Adrenergic Agents; D002839:Chromans; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D007545:Isoproterenol