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Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca²⁺ Sensitivity.

ABSTRACT: Omecamtiv mecarbil (OM) is a pharmacological agent that augments cardiac contractile function by enhancing myofilament Ca²⁺ sensitivity. Given that interventions that increase myofilament Ca²⁺ sensitivity have the potential to alter length-dependent activation (LDA) of cardiac myofilaments, we tested the influence of OM on this fundamental property of the heart. This is significant not only because LDA is prominent in cardiac muscle but also because it contributes to the Frank-Starling law, a mechanism by which the heart increases stroke volume in response to an increase in venous return. We measured steady-state and dynamic contractile indices in detergent-skinned guinea pig (Cavia porcellus) cardiac muscle fibers in the absence and presence of 0.3 and 3.0 ?M OM at two different sarcomere lengths (SLs), short SL (1.9 ?m) and long SL (2.3 ?m). Myofilament Ca²⁺ sensitivity, as measured by pCa₅₀ (-log of [Ca²⁺]_free concentration required for half-maximal activation), increased significantly at both short and long SLs in OM-treated fibers when compared to untreated fibers; however, the magnitude of increase in pCa₅₀ was twofold greater at short SL than at long SL. A consequence of this greater increase in pCa₅₀ at short SL was that pCa₅₀ did not increase any further at long SL, suggesting that OM abolished the SL dependency of pCa₅₀. Furthermore, the SL dependency of rate constants of cross-bridge distortion dynamics (c) and force redevelopment (k_tr) was abolished in 0.3-?M-OM-treated fibers. The negative impact of OM on the SL dependency of pCa₅₀, c, and k_tr was also observed in 3.0-?M-OM-treated fibers, indicating that cooperative mechanisms linked to LDA were altered by the OM-mediated effects on cardiac myofilaments.

SUBMITTER: Gollapudi SK

PROVIDER: S-EPMC5567428 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca2+ Sensitivity.

Gollapudi Sampath K SK Reda Sherif M SM Chandra Murali M

Biophysical journal 20170801 4

Omecamtiv mecarbil (OM) is a pharmacological agent that augments cardiac contractile function by enhancing myofilament Ca2+ sensitivity. Given that interventions that increase myofilament Ca2+ sensitivity have the potential to alter length-dependent activation (LDA) of cardiac myofilaments, we tested the influence of OM on this fundamental property of the heart. This is significant not only because LDA is prominent in cardiac muscle but also because it contributes to the Fr ...[more]

PMID: 28834724

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Project description:Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.

Project description:Background and objectiveOmecamtiv mecarbil is a novel selective cardiac myosin activator (myotrope) under investigation for the treatment of heart failure with reduced ejection fraction. The objective of this clinical study was to estimate the effect of varying degrees of renal impairment on the pharmacokinetics of omecamtiv mecarbil single dose (50 mg) under fasted conditions.MethodsThis phase I, open-label, non-randomized, parallel-group study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of omecamtiv mecarbil 50 mg in individuals with normal renal function or mild, moderate, and severe renal impairment, including end-stage renal disease requiring dialysis. Geometric least-squares mean ratios of maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) and 90% confidence intervals were derived for comparisons of renal impairment vs normal renal function. Participants were monitored for adverse events.ResultsThirty-one participants received treatment and completed the study. Geometric mean exposures were similar for participants with renal impairment (AUC∞ range, 2550-3220 h*ng/mL; Cmax range, 78.9-107 ng/mL) and participants with normal renal function (AUC∞, 2790 h*ng/mL; Cmax, 92.6 ng/mL), with geometric least-squares mean ratios of 85.2-125.9. Exposure was similar on dialysis vs non-dialysis days in participants with end-stage renal disease (AUC0-24, 1650 vs 1700 h*ng/mL; Cmax, 100.0 vs 107.0 ng/mL). Four participants (12.9%) reported four treatment-emergent adverse events. No deaths, treatment-emergent adverse events leading to discontinuation, or serious adverse events occurred.ConclusionsOmecamtiv mecarbil pharmacokinetics were not meaningfully affected by renal function or hemodialysis, suggesting the same dosing strategy can be used in individuals with normal renal function or renal impairment. Oral administration of omecamtiv mecarbil was not associated with major tolerability findings. This study supports omecamtiv mecarbil for the treatment of heart failure in individuals with or without renal impairment.

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Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca²⁺ Sensitivity.

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Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca<sup>2+</sup> Sensitivity.

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