Yes / We 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.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/16481 |
| Date | 2018 February 1923 |
| Creators | Hardy, Matthew E., Pervolaraki, E., Bernus, O., White, E. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| 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., CC-BY |
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