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 IKs, IKr, and IK1 current 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 –IKs, IKr, IK1– 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 IKs, IKr, IK1 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 IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKr<IK1<IKs following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of IKs, IKr, IK1 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 anti-arrhythmic drug strategies to treat the hearts exposed to various sympathetic tones.

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility

“…A more interesting possibility is suggested by the results of Banyasz et al . (), who found that, although I Ks was minimal at baseline (0.152 A/F, comparable to our adjusted model), it was rapidly and dramatically enhanced over 13‐fold by β‐adrenergic stimulation (to 2.067 A/F). When run under the same conditions, I Ks in our adjusted model shows good agreement with their baseline data (0.108 A/F), whereas I Ks in the original model (1.883 A/F).…”

“…However, Banyasz et al . () and Rocchetti et al . (; ) observed only minimal I Ks during AP clamp in guinea pig ventricular cardiomyocytes under baseline conditions, in agreement with our results.…”

“…Indeed, Banyasz et al . () show that the ratio of I Ks / I Kr increased from 0.074 at baseline to 1.707 with β‐adrenergic stimulation with 30 n m isoproterenol (when both currents are recorded at –20 mV). This is comparable to the difference between our adjusted model (0.045) and the original model (1.416) when run under the same conditions.…”

“…() (and others finding similarly high I Ks ) were in a different regulatory state compared to our cells and those examined by Banyasz et al . (). More specifically, we hypothesize that cells in some studies may exhibit significant basal PKA‐dependent phosphorylation of the I Ks channel, increasing the importance of I Ks in those cells.…”

Quantitative analysis of the Ca2+‐dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes

“…Dynamic clamp experiments in guinea pig myocytes demonstrated that I Ks was larger than I Kr subsequent to β‐adrenergic stimulation (Banyasz et al . ). This is an important finding because these recordings are in conditions where [Ca 2+ ] i is not buffered and physiological membrane and Ca 2+ dynamics are maintained (Banyasz et al .…”