Abstract
BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionEstimated 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.
Highlights
We have described the utility of phase-space representations of simultaneously measured myoplasmic Ca2+ concentration ([Ca2+]) and left ventricular pressure (LVP) in guinea pig intact hearts during spharmacologic and pathophysiologic interventions [1,2,3,4,5]
In the present study we extended our phase-space analyses of LVP and [Ca2+] [5] using mathematical modeling techniques to examine the effects of ischemia reperfusion (IR) injury on changes elicited by different positive inotropic agents
The results indicate: 1) the four-state model with cooperativity is capable of interpreting changes in central and downstream regulation of contractility due to inotropic drugs in the presence and absence of IR injury in guinea pig isolated hearts from the phase-space relationship between [Ca2+] and LVP; 2) IR injury in the absence of inotropic agents resulted in reduced Ca2+ affinity for TnCA, and decreased cross-bridge kinetics; 3) dopamine enhanced cross-bridge kinetics before and after ischemia; 4) dopamine decreased myofilament Ca2+ affinity before ischemia but enhanced this affinity after ischemia; 5) in contrast, dobutamine reduced myofilament Ca2+ sensitivity, and increased cross-bridge kinetics before and after ischemia; and 6) digoxin and levosimendan improved
Summary
We have described the utility of phase-space representations of simultaneously measured myoplasmic Ca2+ concentration ([Ca2+]) and left ventricular pressure (LVP) in guinea pig intact hearts during spharmacologic and pathophysiologic interventions [1,2,3,4,5]. Three pharmacological classes of positive inotropes were examined: dopaminergic and adrenergic agonists (i.e., dopamine, dobutamine), a Na+/K+ ATPase inhibitor (i.e., digoxin), and a so-called myofilament Ca2+ sensitizer with phosphodiesterase inhibiting properties (i.e., levosimendan) While each of these drugs increases myoplasmic [Ca2+] ("upstream" mechanism), their effects on Ca2+ binding to troponin C ("central" mechanism) and actinomyosin cross-bridge cycling ("downstream" mechanism) remain unexplored or controversial. 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
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