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, 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.
Department of Comparative, Cellular and Molecular Biology, Universidad Favaloro, Buenos Aires, Argentina. Electronic address: cardiomod@gmail.com.
Jorge A
JA
Negroni
Department of Pharmacology, University of California Davis, CA, USA.
Stefano
S
Morotti
Department of Comparative, Cellular and Molecular Biology, Universidad Favaloro, Buenos Aires, Argentina.
Elena C
EC
Lascano
Department of Neurobiology, Physiology and Behavior, University of California Davis, CA, USA.
Aldrin V
AV
Gomes
Department of Pharmacology, University of California Davis, CA, USA.
Eleonora
E
Grandi
Department of Pharmacology, University of California Davis, CA, USA.
José L
JL
Puglisi
Department of Pharmacology, University of California Davis, CA, USA. Electronic address: dmbers@ucdavis.edu.
Donald M
DM
Bers
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D064211:Connectin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects* / Q000502:physiology; D011433:Propranolol / Q000494:pharmacology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D012984:Software; D000099211:Phospholamban
D018663:Adrenergic Agents; D002118:Calcium; D002135:Calcium-Binding Proteins; D064211:Connectin; D007545:Isoproterenol; D011433:Propranolol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D000099211:Phospholamban
Ca(2+) sensitivity; Contractile model; Cross-bridge cycling; Myocyte model; β-adrenergic