Abstract 2948: Myofilament Calcium Sensitivity: The Heart of Pyruvate’s Inotropic Mechanism
Positive inotropic therapy has traditionally been accomplished by agents that alter intracellular calcium concentrations through β-adrenergic stimulation of the heart or phosphodiesterase inhibition. Pyruvate, when administered in supraphysiologic concentrations, has unique inotropic properties; it can increase force without significant increase in cardiac rate or decrease in cardiac economy. The molecular mechanism of pyruvate’s inotropic mechanism is not known. We hypothesize that changes in myofilament calcium sensitivity are the main determinants of pyruvate’s inotropic effect.
Methods: We utilize ultra thin rabbit heart trabeculae (diameter <0.2 mm) at near physiologic conditions to assess contractile properties. After obtaining steady state contraction parameters, pyruvate (10 mM) is perfused. By utilizing bis-fura-2 to monitor [Ca++]i and under conditions of control versus SR block (ryanodine 1μmol and cyclopiazonic acid 10μmol) we characterized the direct effects of pyruvate on calcium transients and developed force by isolating them from pyruvate’s effects on the SR. In order to study the effects of pyruvate on the force calcium relationship at 37oC, a recently developed potassium contracture technique was utilized.
Results: Under SR block systolic calcium is practically unchanged compared to the relatively large (175%) increase in force development seen with pyruvate infusion (n=8). In the potassium contracture experiments we observed a marked change in pCa50: an increase of 0.17±0.04 units from 6.17±0.06 baseline to peak (p<0.005, n=6) during pyruvate infusion. This change in calcium sensitivity is of similar magnitude to that observed under full β-adrenergic stimulation, indicating a physiological and pharmacologically relevant change.
Conclusion: The data suggest that pyruvate’s inotropic mechanism is primarily due to changes in myofilament calcium sensitivity, and not by affecting intracellular calcium cycling levels primarily. Further elucidating pyruvate’s inotropic mechanism may lead to new therapeutic approaches towards management and understanding of heart failure.