Faculty Collaboration Database

Ischemia reperfusion dysfunction changes model-estimated kinetics of myofilament interaction due to inotropic drugs in isolated hearts. Biomed Eng Online 2006 Mar 02;5:16

Date

03/04/2006

Pubmed ID

16512898

Pubmed Central ID

PMC1431537

DOI

10.1186/1475-925X-5-16

Scopus ID

2-s2.0-33645539806 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

BACKGROUND: The phase-space relationship between simultaneously measured myoplasmic [Ca2+] and isovolumetric left ventricular pressure (LVP) in guinea pig intact hearts is altered by ischemic and inotropic interventions. Our objective was to mathematically model this phase-space relationship between [Ca2+] and LVP with a focus on the changes in cross-bridge kinetics and myofilament Ca2+ sensitivity responsible for alterations in Ca2+-contraction coupling due to inotropic drugs in the presence and absence of ischemia reperfusion (IR) injury.

METHODS: We used a four state computational model to predict LVP using experimentally measured, averaged myoplasmic [Ca2+] transients from unpaced, isolated guinea pig hearts as the model input. Values of model parameters were estimated by minimizing the error between experimentally measured LVP and model-predicted LVP.

RESULTS: We found that IR injury resulted in reduced myofilament Ca2+ sensitivity, and decreased cross-bridge association and dissociation rates. Dopamine (8 microM) reduced myofilament Ca2+ sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 microM) reduced myofilament Ca2+ sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 microM) increased myofilament Ca2+ sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 microM) enhanced myofilament Ca2+ affinity and cross-bridge kinetics only after ischemia.

CONCLUSION: Estimated model parameters reveal mechanistic changes in Ca2+-contraction coupling due to IR injury, specifically the inefficient utilization of Ca2+ for contractile function with diastolic contracture (increase in resting diastolic LVP). The model parameters also reveal drug-induced improvements in Ca2+-contraction coupling before and after IR injury.

Author List

Rhodes SS, Camara AK, Ropella KM, Audi SH, Riess ML, Pagel PS, Stowe DF

Authors

Said Audi PhD Professor in the Biomedical Engineering department at Marquette University
Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of Wisconsin
David F. Stowe MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actin Cytoskeleton
Animals
Calcium
Cardiotonic Agents
Computer Simulation
Dose-Response Relationship, Drug
Drug Therapy, Computer-Assisted
Guinea Pigs
Kinetics
Models, Cardiovascular
Myocardial Contraction
Reperfusion Injury
Treatment Outcome
Ventricular Dysfunction, Left