Electrophysiologic effects of the I-K1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts

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dc.contributor.authorHoeker, Gregory S.en
dc.contributor.authorSkarsfeldt, Mark A.en
dc.contributor.authorJespersen, Thomasen
dc.contributor.authorPoelzing, Stevenen
dc.contributor.departmentBiomedical Engineering and Mechanicsen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.date.accessioned2019-08-28T16:26:07Zen
dc.date.available2019-08-28T16:26:07Zen
dc.date.issued2017-01en
dc.description.abstractThe pentamidine analog PA-6 was developed as a specific inward rectifier potassium current (I-K1) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl2, an established I-K1 inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted I-K1 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 (APD(90)). 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 I-K1 inhibitor, PA-6, are [K+](o)-dependent.en
dc.description.notesThis work was supported in part by the Novo Nordisk Foundation (TJ) and the National Institutes of Health R01 (SP, R01-HL102298).en
dc.description.sponsorshipNovo Nordisk Foundation; National Institutes of Health [R01-HL102298]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.14814/phy2.13120en
dc.identifier.issn2051-817Xen
dc.identifier.issue1en
dc.identifier.othere13120en
dc.identifier.pmid28087819en
dc.identifier.urihttp://hdl.handle.net/10919/93282en
dc.identifier.volume5en
dc.language.isoenen
dc.publisherThe Physiological Societyen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectAction potentialen
dc.subjectconduction velocityen
dc.subjectinward rectifier currenten
dc.subjectpentamidineen
dc.subjectpotassiumen
dc.subjectrepolarizationen
dc.titleElectrophysiologic effects of the I-K1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig heartsen
dc.title.serialPhysiological Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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