Mechanisms of Steeper APD Restitution in Rat Failing Right Ventricular Myocytes

Abstract

Pulmonary artery hypertension (PAH) causes the right ventricle (RV) to become hypertrophied and fail. During this process the RV undergoes electrophysiological remodeling with resultant changes in action potential duration (APD). This study evaluated changes in APD restitution in a rodent model of PAH.Male Wistar rats were given a single i.p. injection of monocrotaline (60 mg/kg) or an equivalent volume of saline. When clinical symptoms of heart failure became apparent (3-4 weeks later) animals were euthanized and the hearts excised. RV myocytes were enzymatically isolated and used for a number of electrophysiological measurements. These included: measurements of APD at pacing rates between 1 and 9 Hz; an action potential (AP) clamp to impose the AP recorded at 1 Hz at pacing rates of 1, 2, 5 and 7 Hz; and measurements of APD during application of increased negative current pulses between 1 and 500 pA in amplitude at 1 and 5 Hz.Myocytes from the failing right ventricle had a significantly longer APD and steeper APD steeper restitution curve compared to sham cells. Despite this greater APD shortening, under action potential clamp, compensation currents in failing myocytes were smaller in amplitude as pacing frequency increased. Consistent with this observation, injection of negative current caused a greater decrease in APD90 in failing cells (P < 0.0001-0.05, n = 6-7 myocytes, ANOVA, Tukeys post-test).These findings show that cells isolated from the monocrotaline treated RV required less current to cause a decrease in APD, which is consistent with an increased membrane resistance. Previous studies have reported a decreased expression of potassium channels in monocrotaline-treated myocytes, which may be a contributing factor responsible for the results observed.Supported by the MRC.