Beta-adrenergic stimulation reverses the IKr-IKs dominant pattern during cardiac action potential

beta-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 beta-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 Ca2+ 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 beta-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 beta-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.