Effects of zacopride, a moderate IK1 channel agonist, on triggered arrhythmia and contractility in human ventricular myocardium

Abstract

Ventricular tachycardia is the leading cause of sudden arrhythmic death in the U.S. Recently, the moderate IK1 channel activator, zacopride, was shown to suppress triggered ventricular tachycardia in rats. Nonetheless, concerns were raised about the possibility of pro-arrhythmic activity after IK1 channel stimulation based on the promising anti-arrhythmic strategy of IK1 blockade in other animal models. Therefore, the goal of the current study was to investigate the ex-vivo effects of zacopride on triggered arrhythmia and contractility in ventricular human myocardium in order to validate data that was solely obtained from animal models. Application of 100 nmol/L isoproterenol and 0.5 mmol/L caffeine led to triggered arrhythmia in isolated cardiac muscles from non-failing and end-stage failing hearts. However, the occurrence of arrhythmia in muscles of non-failing hearts was markedly higher than those of end-stage failing hearts. Interestingly, zacopride eliminated the ex-vivo triggered arrhythmia in these muscles of non-failing and failing hearts in a concentration-dependent manner, with an effective IC50 in the range of 28 to 40 µmol/L. Conversely, in the absence of isoproterenol/caffeine, zacopride led to a negative inotropic effect in a concentration-dependent manner. Reduced cardiac contraction was clearly observed at high zacopride concentration of 200 µmol/L, along with the occurrence of contractile alternans in muscles of non-failing and failing hearts. Zacopride shows promising antiarrhythmic effects against triggered arrhythmia in ventricular human myocardium. However, in the absence of Ca2+ overload/arrhythmia, zacopride, albeit at high concentrations, decreases the force of contraction and increases the likelihood of occurrence of contractile alternans, which may predispose the heart to contractile dysfunction and/or arrhythmia. Overall, our results represent a key step in translating this drug from the benchtop to the bedside in the research area.

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

“…As stated above both time to peak isometric force and isometric relaxation time obtained in our simulations fit well into the range of the respective data obtained on papillary muscles, trabeculae and subepicardial biopsy strips from the human ventricles [45,49,52,56,62,63].…”

“…(B) Time-dependent signals of the concentration of calciumtroponin C complexes ([Ca-TnC]), intracellular Ca 2+ transient ([Ca 2+ ]i), Na + -Ca 2+ exchange current (iNaCa) and inward rectifier K + current (iK1) for isometric and afterloaded contractions at the low afterload Figure 3 shows results of our simulations using TP+M model for a steady state isometric contraction of a sample initially stretched by a preload to a length of 90%L max (where L max corresponds to a sarcomere length equal to 2.23 µm). Both time to peak isometric force and isometric relaxation time obtained in our simulations fit well into the range of the respective data obtained on papillary muscles, trabeculae and subepicardial biopsy strips from the human ventricles [45,49,52,56,62,63]. The isometric signals are superimposed with ones recorded in simulated series of isotonic contractions under various afterloads, at the same initial length of 90% L max .…”

“…10 were obtained at different lengths just when simulating series of steady state isometric contractions at the frequency of 1 Hz. These characteristics really fall into the ranges of values reported both in the cited work [56] and in other experimental works where the data obtained in isometric contractions of the human myocardium at one or another length were provided, although the effect of the differences in the length was not specially studied [45,51,52,63].…”

Force-frequency relationship and early relaxation kinetics are preserved upon sarcoplasmic blockade in human myocardium

“…; Elnakish et al. ), non‐ischemic and ischemic muscles show a rather similar contractile profile, smaller quantitative differences may exist. Overall, since the impact of SR blockade is highly similar in failing and nonfailing tissue, impact of specific patient characteristics such as age or gender is likely not a major factor.…”

“…Immediately after the hearts were explanted, they were coronaryperfused with ice-cold cardioplegic solution containing: 110 mmol/L NaCl, 0.5 mmol/L CaCl 2 , 16 mmol/L KCl, 16 mmol/L MgCl 2 6H 2 O, and 10 mmol/L NaHCO 3 at pH 7.4. In~20 min after explantation, the hearts were transported to the laboratory for experiments (Milani-Nejad et al 2015;Elnakish et al 2017).…”