title: Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.
abstract: β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.
authors.affiliation: Department of Pharmacology, University of California, 2221 Tupper Hall, 451 Health Science Drive, Davis, CA, 95616, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Banyasz
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jian
authors.forename: Balazs
authors.initials: B
authors.lastname: Horvath
authors.forename: Shaden
authors.initials: S
authors.lastname: Khabbaz
authors.forename: Leighton T
authors.initials: LT
authors.lastname: Izu
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen-Izu
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D018663:Adrenergic Agents; D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium