Β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model. (April 2015)

• Record Type: Journal Article
• Authors: Negroni, Jorge A.; Morotti, Stefano; Lascano, Elena C.; Gomes, Aldrin V.; Grandi, Eleonora; Puglisi, José L.; Bers, Donald M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 81(2015:Apr.)
• Page Start: 162
• Page End: 175
• Publication Date: 2015-04
• Subjects: β-adrenergic -- Myocyte model -- Contractile model -- Ca2+ sensitivity -- Cross-bridge cycling; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.02.014
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca 2+ 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 Ca 2+ handling, Ca 2+, 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 Ca 2+ 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 Ca 2+ transient amplitude and kinetics. It also replicated the behavior of force–Ca 2+, 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 Ca 2+ channels or phospholamban limited Ca 2+ transients and contractile responses in parallel, while blocking phospholemman and K + channel (IKs ) effects enhanced Ca 2+ and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca 2+ (due to greater Ca 2+ buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca 2+ 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. Highlights: β-AS effects on cardiac contraction are analyzed with a new computer model. The model reproduces a range of experiments involving force and length changes. Impact of PKA targets to β-AS effects on AP, Ca 2 + and contraction is studied. ICa, PLB, PLM and IKs effects dominate in the β-AS increase in Ca 2 + transients. Increased XBcy compensates for lower myofilament Ca 2 + sensitivity during inotropy.