| Summary: | <p>Abstract</p> <p>Background</p> <p>The phase-space relationship between simultaneously measured myoplasmic [Ca<sup>2+</sup>] 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 [Ca<sup>2+</sup>] and LVP with a focus on the changes in cross-bridge kinetics and myofilament Ca<sup>2+ </sup>sensitivity responsible for alterations in Ca<sup>2+</sup>-contraction coupling due to inotropic drugs in the presence and absence of ischemia reperfusion (IR) injury.</p> <p>Methods</p> <p>We used a four state computational model to predict LVP using experimentally measured, averaged myoplasmic [Ca<sup>2+</sup>] 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.</p> <p>Results</p> <p>We found that IR injury resulted in reduced myofilament Ca<sup>2+ </sup>sensitivity, and decreased cross-bridge association and dissociation rates. Dopamine (8 μM) reduced myofilament Ca<sup>2+ </sup>sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 μM) reduced myofilament Ca<sup>2+ </sup>sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 μM) increased myofilament Ca<sup>2+ </sup>sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 μM) enhanced myofilament Ca<sup>2+ </sup>affinity and cross-bridge kinetics only after ischemia.</p> <p>Conclusion</p> <p>Estimated model parameters reveal mechanistic changes in Ca<sup>2+</sup>-contraction coupling due to IR injury, specifically the inefficient utilization of Ca<sup>2+ </sup>for contractile function with diastolic contracture (increase in resting diastolic LVP). The model parameters also reveal drug-induced improvements in Ca<sup>2+</sup>-contraction coupling before and after IR injury.</p>
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