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β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model

  • Author(s): Negroni, JA
  • Morotti, S
  • Lascano, EC
  • Gomes, AV
  • Grandi, E
  • Puglisi, JL
  • Bers, DM
  • et al.

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© 2015 Elsevier Ltd. A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca2+transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca2+handling, Ca2+, K+and Cl-currents, and Na+/K+-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca2+sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca2+transient amplitude and kinetics. It also replicated the behavior of force-Ca2+, release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca2+channels or phospholamban limited Ca2+transients and contractile responses in parallel, while blocking phospholemman and K+channel (IKs) effects enhanced Ca2+and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca2+(due to greater Ca2+buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca2+transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa and XBcy have greater impact on isometric and isotonic contraction, respectively.

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