The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat

L. Nagy, Kovács, B. Bõdi, E. T. Pásztor, G. Fülöp, A. Tõth, I. Édes, Z. Papp

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Abstract

Background and Purpose Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. Experimental Approaches Ca2+-dependent active force production (Factive), its Ca2+ sensitivity (pCa50), the kinetic characteristics of Ca2+-regulated activation and relaxation, and Ca2+-independent passive force (Fpassive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM). Key Results In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 μM OM (EC50: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. Conclusions and Implications OM acted as a Ca2+-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.

Original languageEnglish
Pages (from-to)4506-4518
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number18
DOIs
Publication statusPublished - Sep 1 2015

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Cardiac Myosins
Skeletal Muscle Fibers
Cardiac Myocytes
Calcium
Diaphragm
Muscles
omecamtiv mecarbil
Systolic Heart Failure
Inbred WKY Rats
Octoxynol

ASJC Scopus subject areas

  • Pharmacology

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The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat. / Nagy, L.; Kovács; Bõdi, B.; Pásztor, E. T.; Fülöp, G.; Tõth, A.; Édes, I.; Papp, Z.

In: British Journal of Pharmacology, Vol. 172, No. 18, 01.09.2015, p. 4506-4518.

Research output: Contribution to journalArticle

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AU - Nagy, L.

AU - Kovács,

AU - Bõdi, B.

AU - Pásztor, E. T.

AU - Fülöp, G.

AU - Tõth, A.

AU - Édes, I.

AU - Papp, Z.

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N2 - Background and Purpose Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. Experimental Approaches Ca2+-dependent active force production (Factive), its Ca2+ sensitivity (pCa50), the kinetic characteristics of Ca2+-regulated activation and relaxation, and Ca2+-independent passive force (Fpassive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM). Key Results In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 μM OM (EC50: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. Conclusions and Implications OM acted as a Ca2+-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.

AB - Background and Purpose Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. Experimental Approaches Ca2+-dependent active force production (Factive), its Ca2+ sensitivity (pCa50), the kinetic characteristics of Ca2+-regulated activation and relaxation, and Ca2+-independent passive force (Fpassive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM). Key Results In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 μM OM (EC50: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. Conclusions and Implications OM acted as a Ca2+-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.

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