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

J Mol Cell Cardiol. 2015 Apr;81:162-75. doi: 10.1016/j.yjmcc.2015.02.014. Epub 2015 Feb 25.

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.

Keywords: Ca(2+) sensitivity; Contractile model; Cross-bridge cycling; Myocyte model; β-adrenergic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Adrenergic Agents / pharmacology*
  • Animals
  • Calcium / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Computer Simulation
  • Connectin / genetics
  • Connectin / metabolism
  • Gene Expression Regulation
  • Heart Ventricles / cytology
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Isoproterenol / pharmacology*
  • Models, Cardiovascular*
  • Myocardial Contraction / drug effects*
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myofibrils / drug effects*
  • Myofibrils / physiology
  • Propranolol / pharmacology*
  • Rabbits
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Signal Transduction
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Software

Substances

  • Adrenergic Agents
  • Calcium-Binding Proteins
  • Connectin
  • phospholamban
  • Propranolol
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sodium-Potassium-Exchanging ATPase
  • Isoproterenol
  • Calcium