Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats

Abstract

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 9 Hz. Action potential waveforms recorded at 1 Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7 Hz 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 (5 μM) ranolazine or the intracellular Ca2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller in MCT myocytes 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.

Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension

“…8 ) and NCX current (Fig. S4) and have recently reported that membrane stability is decreased in these cells [ 22 ]. Thus, the decrease in WCEs in response to BB can be explained by the decrease in SR Ca 2+ load and intermediate level of Kir2.1 expression in MCT + BB myocytes.…”

“…In addition we have previously shown that the contraction-frequency relationship in MCT myocytes is influenced by BB via expression of creatine kinase [ 15 , 16 ]. Repolarization profile can modulate Ca 2+ handling [ 5 ] and we have shown that in MCT myocytes the stimulation frequency dependent fall in contraction is, at least in part, caused by the stimulation frequency dependent fall in action potential duration (APD) [ 3 , 22 ]. Therefore, the prolonged APD and QT interval occurring in the MCT model may facilitate greater SR load through enhanced Ca 2+ entry, while steeper APD restitution contributes to the steeper stimulation frequency dependent fall in Ca 2+ transient amplitude [ 3 , 22 ].…”

Compensated right ventricular function of the onset of pulmonary hypertension in a rat model depends on chamber remodeling and contractile augmentation

“…25–28 Some prominent studies indicate the presence of a proarrhythmic substrate in hearts of MCT-treated rats, and among the causes of sudden death are the changes in Ca 2+ and K + channel activity and electrical restitution. 29–32…”

“…[25][26][27][28] Some prominent studies indicate the presence of a proarrhythmic substrate in hearts of MCT-treated rats, and among the causes of sudden death are the changes in Ca 2þ and K þ channel activity and electrical restitution. [29][30][31][32] Pulmonary arterial stiffness increases in late PAH Pulmonary arterial stiffening markedly increased and became significantly different from the control group to the MCT-injected rats after three weeks. Pulmonary arterial elastance E a values increased as PAH advanced, which has also been reported by other groups when using the rat MCT model: Yin et al from 0.5 AE 0.14 to 0.79 AE 0.3 mmHg/mL; 18 and de Man et al from 0.15 to 1.0 mmHg/mL.…”

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length

“…In contrast to mice, recordings in rat preparations typically do not demonstrate shortening of APD 90 at fast pacing rates ( Benoist et al, 2011 , 2012 ). However, APD restitution has been observed in a rat model of pulmonary hypertension and was recently implicated in the induction of negative mechanical restitution in this model ( Hardy et al, 2018 ).…”