Pharmacological inhibition of I-K1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness
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- Pharmacological inhibition of IK1 by PA‐6 in isolated rat hearts affects ventricular repolarization and refractoriness
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The inwardly rectifying potassium current (IK1) conducted through Kir2.X
channels contribute to repolarization of the cardiac action potential and to
stabilization of the resting membrane potential in cardiomyocytes. Our aim
was to investigate the effect of the recently discovered IK1 inhibitor PA-6 on
action potential repolarization and refractoriness in isolated rat hearts. Transiently
transfected HEK-293 cells expressing IK1 were voltage-clamped with
ramp protocols. Langendorff-perfused heart experiments were performed on
male Sprague–Dawley rats, effective refractory period, Wenckebach cycle
length, and ventricular effective refractory period were determined following
200 nmol/L PA-6 perfusion. 200 nmol/L PA-6 resulted in a significant timelatency
in drug effect on the IK1 current expressed in HEK-293 cells, giving
rise to a maximal effect at 20 min. In the Langendorff-perfused heart experiments,
PA-6 prolonged the ventricular action potential duration at 90% repolarization
(from 41.8 6.5 msec to 72.6 21.1 msec, 74% compared to
baseline, P < 0.01, n = 6). In parallel, PA-6 significantly prolonged the ventricular
effective refractory period compared to baseline (from 34.8 4.6
msec to 58.1 14.7 msec, 67%, P < 0.01, n = 6). PA-6 increased the shortterm
beat-to-beat variability and ventricular fibrillation was observed in two
of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered
following PA-6 application. The results show that pharmacological inhibition
of cardiac IK1 affects ventricular action potential repolarization and refractoriness
and increases the risk of ventricular arrhythmia in isolated rat hearts.
Original language | English |
---|---|
Article number | e12734 |
Journal | Physiological Reports |
Volume | 4 |
Issue number | 8 |
Number of pages | 11 |
ISSN | 2051-817X |
DOIs | |
Publication status | Published - Apr 2016 |
- Action potential, I-K1, inward rectifier current, Kir2.x channels, pentamidine
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