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Background  The phase-space relationship between simultaneously measured myoplasmic [Ca 2+ ] 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 2+ ] and LVP with a focus on the changes in cross-bridge kinetics and myofilament Ca 2+  sensitivity responsible for alterations in Ca 2+ -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 [Ca 2+ ] 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 Ca 2+  sensitivity, and decreased cross-bridge association and dissociation rates. Dopamine (8 μM) reduced myofilament Ca 2+  sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 μM) reduced myofilament Ca 2+  sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 μM) increased myofilament Ca 2+  sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 μM) enhanced myofilament Ca 2+  affinity and cross-bridge kinetics only after ischemia.    Conclusion  Estimated model parameters reveal mechanistic changes in Ca 2+ -contraction coupling due to IR injury, specifically the inefficient utilization of Ca 2+  for contractile function with diastolic contracture (increase in resting diastolic LVP). The model parameters also reveal drug-induced improvements in Ca 2+ -contraction coupling before and after IR injury.

Ischemia reperfusion dysfunction changes model-estimated kinetics of myofilament interaction due to inotropic drugs in isolated hearts