Electrophysiologic effects of the IK1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts

Gregory S Hoeker, Mark A Skarsfeldt, Thomas Jespersen, Steven Poelzing

5 Citations (Scopus)
57 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere13120
JournalPhysiological Reports
Volume5
Issue number1
Number of pages10
ISSN2051-817X
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Action Potentials/drug effects
  • Animals
  • Anthraquinones/administration & dosage
  • Barium Compounds/administration & dosage
  • Chlorides/administration & dosage
  • Electrophysiological Phenomena
  • Guinea Pigs
  • Heart/physiology
  • Heart Conduction System/drug effects
  • Heart Ventricles/drug effects
  • Hypokalemia/physiopathology
  • Male
  • Pentamidine/analogs & derivatives
  • Potassium/metabolism
  • Potassium Channel Blockers/administration & dosage
  • Potassium Channels/drug effects
  • Pyridinium Compounds/analysis
  • Voltage-Sensitive Dye Imaging/methods

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