Pharmacological inhibition of I-K1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness
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Pharmacological inhibition of I-K1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness. / Skarsfeldt, Mark A.; Carstensen, Helena; Skibsbye, Lasse; Tang, Chuyi; Buhl, Rikke; Bentzen, Bo H.; Jespersen, Thomas.
I: Physiological Reports, Bind 4, Nr. 8, e12734, 04.2016.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Pharmacological inhibition of I-K1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness
AU - Skarsfeldt, Mark A.
AU - Carstensen, Helena
AU - Skibsbye, Lasse
AU - Tang, Chuyi
AU - Buhl, Rikke
AU - Bentzen, Bo H.
AU - Jespersen, Thomas
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
KW - Action potential
KW - I-K1
KW - inward rectifier current
KW - Kir2.x channels
KW - pentamidine
U2 - 10.14814/phy2.12734
DO - 10.14814/phy2.12734
M3 - Journal article
C2 - 27117805
VL - 4
JO - Physiological Reports
JF - Physiological Reports
SN - 2051-817X
IS - 8
M1 - e12734
ER -
ID: 164885473