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dc.contributor.authorHardy, Matthew E.*
dc.contributor.authorPervolaraki, E.*
dc.contributor.authorBernus, O.*
dc.contributor.authorWhite, E.*
dc.date.accessioned2018-07-13T15:20:43Z
dc.date.available2018-07-13T15:20:43Z
dc.date.issued2018-03-12
dc.identifier.citationHardy ME, Pervolaraki E, Bernus O and White E (2018) Dynamic action potential restitution contributes mechanical restitution in right ventricular myocytes from pulmonary hypertensive rats. Frontiers in Physiology. 9: Article 205.en_US
dc.identifier.urihttp://hdl.handle.net/10454/16481
dc.descriptionyesen_US
dc.description.abstractWe investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9Hz. Action potential waveforms recorded at 1Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na+-channel blocker (5μM) ranolazine or the intracellular Ca2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller inMCTmyocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus, our study links electrical restitution remodeling to a defining mechanical characteristic of heart failure, the reduced ability to respond to an increase in demand.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.3389/fphys.2018.00205en_US
dc.rights© 2018 Hardy, Pervolaraki, Bernus and White. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.subjectPulmonary artery hypertensionen_US
dc.subjectAction potential duration (APD) restitutionen_US
dc.subjectMechanical restitutionen_US
dc.subjectRight heart failureen_US
dc.subjectAction potential clampen_US
dc.subjectRight ventricular myocytesen_US
dc.titleDynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Ratsen_US
dc.status.refereedyesen_US
dc.date.Accepted2018-02-23
dc.typeArticleen_US
dc.type.versionPublished versionen_US
refterms.dateFOA2018-07-29T02:38:47Z


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