Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations
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Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations. / Rhoden, Alexandra; Schulze, Thomas; Pietsch, Niels; Christ, Torsten; Hansen, Arne; Eschenhagen, Thomas.
in: AM J PHYSIOL-HEART C, Jahrgang 322, Nr. 3, 01.03.2022, S. H373-H385.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations
AU - Rhoden, Alexandra
AU - Schulze, Thomas
AU - Pietsch, Niels
AU - Christ, Torsten
AU - Hansen, Arne
AU - Eschenhagen, Thomas
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function, and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analysis of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared with effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time to peak under all conditions (maximally two- to threefold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increased under isometric conditions, again with biphasic concentration dependency. Diastolic tension concentration dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.NEW & NOTEWORTHY We developed a novel setup allowing precise control of preload of EHT and characterized effects of the myosin activator OM. OM not only exerted contraction-slowing and positive inotropic effects but also increased diastolic tension. Effect size and direction varied between species, auxotonic and isometric conditions, concentration, and time. We also observed OM-induced increase of mitochondrial ROS, which has not been observed before and may explain part of the effects on contractility.
AB - Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function, and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analysis of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared with effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time to peak under all conditions (maximally two- to threefold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increased under isometric conditions, again with biphasic concentration dependency. Diastolic tension concentration dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.NEW & NOTEWORTHY We developed a novel setup allowing precise control of preload of EHT and characterized effects of the myosin activator OM. OM not only exerted contraction-slowing and positive inotropic effects but also increased diastolic tension. Effect size and direction varied between species, auxotonic and isometric conditions, concentration, and time. We also observed OM-induced increase of mitochondrial ROS, which has not been observed before and may explain part of the effects on contractility.
KW - Adenosine Triphosphate/metabolism
KW - Animals
KW - Calcium/metabolism
KW - Cardiotonic Agents/pharmacology
KW - Cell Line
KW - Cells, Cultured
KW - Cellular Reprogramming Techniques/methods
KW - Humans
KW - Induced Pluripotent Stem Cells/cytology
KW - Mitochondria, Heart/drug effects
KW - Myocardial Contraction
KW - Myocytes, Cardiac/cytology
KW - Rats
KW - Rats, Wistar
KW - Reactive Oxygen Species/metabolism
KW - Urea/analogs & derivatives
U2 - 10.1152/ajpheart.00534.2021
DO - 10.1152/ajpheart.00534.2021
M3 - SCORING: Journal article
C2 - 35030072
VL - 322
SP - H373-H385
JO - AM J PHYSIOL-HEART C
JF - AM J PHYSIOL-HEART C
SN - 0363-6135
IS - 3
ER -