title: Electrophysiologic effects of the IK1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts.
abstract: The pentamidine analog PA-6 was developed as a specific inward rectifier potassium current (IK1) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl2, an established IK1inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted IK1inhibition 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 APD90was 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 APD90during hypokalemia (2 mmol/L [K+]o), although to a lesser degree than observed at 4.56 mmol/L [K+]oIn 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 APD90to a lesser degree, but profoundly increased CV Thus, in intact guinea pig hearts, the electrophysiologic effects of the IK1inhibitor, PA-6, are [K+]o-dependent.
authors.affiliation: Biomedical Engineering and Mechanics, Center for Heart and Regenerative Medicine, Virginia Tech Virginia Tech Carilion Research Institute, Roanoke, Virginia.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hoeker
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Skarsfeldt
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
authors.affiliation: Biomedical Engineering and Mechanics, Center for Heart and Regenerative Medicine, Virginia Tech Virginia Tech Carilion Research Institute, Roanoke, Virginia poelzing@vtc.vt.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage / Q000494:pharmacology*; D017609:Barium Compounds / Q000008:administration & dosage / Q000494:pharmacology; D002712:Chlorides / Q000008:administration & dosage / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007008:Hypokalemia / Q000503:physiopathology; D008297:Male; D010419:Pentamidine / Q000031:analogs & derivatives*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011726:Pyridinium Compounds / Q000032:analysis / Q000378:metabolism; D056969:Voltage-Sensitive Dye Imaging / Q000379:methods
chemical_list: D000880:Anthraquinones; D017609:Barium Compounds; D002712:Chlorides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011726:Pyridinium Compounds; C474094:ptilometric acid 6-O-sulfate; C024986:barium chloride; D010419:Pentamidine; C050019:1-(3-sulfonatopropyl)-4-(beta)(2-(di-n-butylamino)-6-naphthylvinyl)pyridinium betaine; D011188:Potassium
keywords: Action potential; conduction velocity; inward rectifier current; pentamidine; potassium; repolarization