Background:
Rapid delayed rectifier K
+
current (I
Kr
) and late Na
+
current (I
NaL
) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death.
Methods:
Physiological self AP-clamp was used to measure I
NaL
and I
Kr
during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between I
Kr
and I
NaL
affects repolarization stability in health and disease conditions.
Results:
We found comparable amount of net charge carried by I
Kr
and I
NaL
during the physiological AP, suggesting that outward K
+
current via I
Kr
and inward Na
+
current via I
NaL
are in balance during physiological repolarization. Remarkably, I
Kr
and I
NaL
integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block I
Kr
(mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na
+
channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit I
NaL
sufficiently restored APD to control in both cases. Importantly, I
NaL
inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I
NaL
inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by I
NaL
inhibition, increased by I
Kr
inhibition, and restored by combined I
NaL
and I
Kr
inhibitions.
Conclusions:
Our data demonstrate that I
Kr
and I
NaL
are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities.
Visual Overview:
A
visual overview
is available for this article.
The hERG channel activator, RPR260243, enhances protective IKr current early in the refractory period reducing arrhythmogenicity in zebrafish hearts
