TY - JOUR
T1 - Electrophysiologic effects of the IK1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts
AU - Hoeker, Gregory S
AU - Skarsfeldt, Mark A
AU - Jespersen, Thomas
AU - Poelzing, Steven
N1 - © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - The pentamidine analog PA-6 was developed as a specific inward rectifier potassium current (IK 1) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl2, an established IK 1 inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted IK 1 inhibition similarly affects ventricular electrophysiology. The aim of this study was to determine the effects of PA-6 on cardiac repolarization and conduction in Langendorff-perfused guinea pig hearts. PA-6 (200 nm) or vehicle was perfused into ex-vivo guinea pig hearts for 60 min. Hearts were optically mapped with di-4-ANEPPS to quantify CV and APD at 90% repolarization (APD90). Ventricular APD90 was significantly prolonged in hearts treated with PA-6 (115 ± 2% of baseline; P < 0.05), but not vehicle (105 ± 2% of baseline). PA-6 slightly, but significantly, increased transverse CV by 7%. PA-6 significantly prolonged APD90 during hypokalemia (2 mmol/L [K+]o), although to a lesser degree than observed at 4.56 mmol/L [K+]o. In contrast, the effect of PA-6 on CV was more pronounced during hypokalemia, where transverse CV with PA-6 (24 ± 2 cm/sec) was significantly faster than with vehicle (13 ± 3 cm/sec, P < 0.05). These results show that under normokalemic conditions, PA-6 significantly prolonged APD90, whereas its effect on CV was modest. During hypokalemia, PA-6 prolonged APD90 to a lesser degree, but profoundly increased CV. Thus, in intact guinea pig hearts, the electrophysiologic effects of the IK 1 inhibitor, PA-6, are [K+]o-dependent.
AB - The pentamidine analog PA-6 was developed as a specific inward rectifier potassium current (IK 1) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl2, an established IK 1 inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted IK 1 inhibition similarly affects ventricular electrophysiology. The aim of this study was to determine the effects of PA-6 on cardiac repolarization and conduction in Langendorff-perfused guinea pig hearts. PA-6 (200 nm) or vehicle was perfused into ex-vivo guinea pig hearts for 60 min. Hearts were optically mapped with di-4-ANEPPS to quantify CV and APD at 90% repolarization (APD90). Ventricular APD90 was significantly prolonged in hearts treated with PA-6 (115 ± 2% of baseline; P < 0.05), but not vehicle (105 ± 2% of baseline). PA-6 slightly, but significantly, increased transverse CV by 7%. PA-6 significantly prolonged APD90 during hypokalemia (2 mmol/L [K+]o), although to a lesser degree than observed at 4.56 mmol/L [K+]o. In contrast, the effect of PA-6 on CV was more pronounced during hypokalemia, where transverse CV with PA-6 (24 ± 2 cm/sec) was significantly faster than with vehicle (13 ± 3 cm/sec, P < 0.05). These results show that under normokalemic conditions, PA-6 significantly prolonged APD90, whereas its effect on CV was modest. During hypokalemia, PA-6 prolonged APD90 to a lesser degree, but profoundly increased CV. Thus, in intact guinea pig hearts, the electrophysiologic effects of the IK 1 inhibitor, PA-6, are [K+]o-dependent.
KW - Action Potentials/drug effects
KW - Animals
KW - Anthraquinones/administration & dosage
KW - Barium Compounds/administration & dosage
KW - Chlorides/administration & dosage
KW - Electrophysiological Phenomena
KW - Guinea Pigs
KW - Heart/physiology
KW - Heart Conduction System/drug effects
KW - Heart Ventricles/drug effects
KW - Hypokalemia/physiopathology
KW - Male
KW - Pentamidine/analogs & derivatives
KW - Potassium/metabolism
KW - Potassium Channel Blockers/administration & dosage
KW - Potassium Channels/drug effects
KW - Pyridinium Compounds/analysis
KW - Voltage-Sensitive Dye Imaging/methods
U2 - 10.14814/phy2.13120
DO - 10.14814/phy2.13120
M3 - Journal article
C2 - 28087819
SN - 2051-817X
VL - 5
JO - Physiological Reports
JF - Physiological Reports
IS - 1
M1 - e13120
ER -