© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Rapid component IKr of the guinea-pig cardiac delayed rectifier K+ current is inhibited by β1-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways
Department of Cardiology, University of Heidelberg Medical School, Bergheimerstrasse 58, D-69115 Heidelberg, Germany
* Corresponding author. Tel.: +49-6221-568-682; fax: +49-6221-565-515 johann_kiehn{at}ukl.uni-heidelberg.de
Objective: The antiarrhythmic potential of betablockers contributes to their beneficial effects in the treatment of cardiac diseases, although the molecular basis of their class II antiarrhythmic action has not been clarified yet. Methods: To investigate a putative functional link between β-adrenoreceptors and the fast component of cardiac delayed rectifier K+ channels (IKr), whole-cell patch-clamp experiments were performed with isolated guinea-pig ventricular myocytes. Tail currents of IKr were measured at –40 mV after short (200 ms) test pulses to +40 mV. Results: After application of the unspecific β-receptor agonist isoproterenol (10 µM) for 12 min, the IKr tail current was decreased by 72%, with an IC50 of 1.4 µM. The specific β1-blocker CGP207120A (10 µM) significantly attenuated the isoproterenol effect (net 24% decrease). The specific β1-agonist xamoterol (10 µM), could mimic the isoproterenol effect (58% decrease). Modulators of β2- or β3-adrenoreceptors were far less effective. When isoproterenol or xamoterol were combined with KT5720 (2.5 µM), a specific inhibitor of protein kinase A (PKA), their effects were drastically reduced, indicating that PKA presumably mediates the β1-adrenergic inhibition of IKr. Tail current reductions by cAMP, forskolin, PKA catalytic subunit and a combination of PKA holoenzyme and cAMP support an involvement of PKA in the regulation of IKr. Conclusions: The functional link between IKr and the β1-adrenergic receptor involving PKA may play an important role in arrhythmogenesis and contribute to the antiarrhythmic action of clinically used β1-blockers.
KEYWORDS Adrenergic (ant)agonists; Antiarrhythmic agents; K-channel; Protein kinases
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