title: Rapid component I(Kr) of the guinea-pig cardiac delayed rectifier K(+) current is inhibited by beta(1)-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways.
abstract: 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 beta-adrenoreceptors and the fast component of cardiac delayed rectifier K(+) channels (I(Kr)), whole-cell patch-clamp experiments were performed with isolated guinea-pig ventricular myocytes. Tail currents of I(Kr) were measured at -40 mV after short (200 ms) test pulses to +40 mV.
  
  
  RESULTS
  After application of the unspecific beta-receptor agonist isoproterenol (10 microM) for 12 min, the I(Kr) tail current was decreased by 72%, with an IC(50) of 1.4 microM. The specific beta(1)-blocker CGP207120A (10 microM) significantly attenuated the isoproterenol effect (net 24% decrease). The specific beta(1)-agonist xamoterol (10 microM), could mimic the isoproterenol effect (58% decrease). Modulators of beta(2)- or beta(3)-adrenoreceptors were far less effective. When isoproterenol or xamoterol were combined with KT5720 (2.5 microM), a specific inhibitor of protein kinase A (PKA), their effects were drastically reduced, indicating that PKA presumably mediates the beta(1)-adrenergic inhibition of I(Kr). 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 I(Kr).
  
  
  CONCLUSIONS
  The functional link between I(Kr) and the beta(1)-adrenergic receptor involving PKA may play an important role in arrhythmogenesis and contribute to the antiarrhythmic action of clinically used beta(1)-blockers.
authors.affiliation: Department of Cardiology, University of Heidelberg Medical School, Bergheimerstrasse 58, D-69115 Heidelberg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Karle
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Sven
authors.initials: S
authors.lastname: Kathöfer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schoels
authors.forename: Johann
authors.initials: J
authors.lastname: Kiehn
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D017307:Xamoterol / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D024661:Potassium Channels, Inwardly Rectifying; D011758:Pyrroles; D005576:Colforsin; C057416:KT 5720; D017307:Xamoterol; C049763:CGP 20712A; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol