Ischemia Reperfusion Dysfunction Changes Model-estimated Kinetics of Myofilament Interaction Due to Inotropic Drugs in Isolated Hearts

Authors

Samhita S. Rhodes, Medical College of Wisconsin
Amadou KS Camara, Medical College of Wisconsin
Kristina M. Ropella, Marquette UniversityFollow
Said H. Audi, Marquette UniversityFollow
Matthias L. Riess, Medical College of Wisconsin
Paul S. Pagel, Marquette University
David F. Stowe, Marquette University

Document Type

Article

Language

eng

Publication Date

3-2006

Publisher

BioMed Central

Source Publication

BioMedical Engineering OnLine

Source ISSN

1475-925X

Original Item ID

DOI: 10.1186/1475-925X-5-16

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 μM) reduced myofilament Ca²⁺ sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 μM) reduced myofilament Ca²⁺ sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 μM) increased myofilament Ca²⁺ sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 μM) 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.

Comments

Published version. BioMedical Engineering OnLine, Vol. 5, No. 16 (March 2006). DOI. © 2006 BioMed Central.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.

Recommended Citation

Rhodes, Samhita S.; Camara, Amadou KS; Ropella, Kristina M.; Audi, Said H.; Riess, Matthias L.; Pagel, Paul S.; and Stowe, David F., "Ischemia Reperfusion Dysfunction Changes Model-estimated Kinetics of Myofilament Interaction Due to Inotropic Drugs in Isolated Hearts" (2006). Biomedical Engineering Faculty Research and Publications. 261.
https://epublications.marquette.edu/bioengin_fac/261