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

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 (I_Ks) 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.