Isolated rabbit working heart function during progressive inhibition of myocardial SERCA activity
Abstract
The extent to which sarcoplasmic reticulum Ca(2+)ATPase (SERCA) activity alone determines left ventricular (LV) pump function is unknown. To correlate SERCA activity with hemodynamic function of rabbit LV during thapsigargin perfusion. Isolated rabbit hearts were perfused in working heart configuration, and LV pump function was assessed using a pressure-volume catheter. Rapid and complete (>95%) inhibition of SERCA was associated with a moderate decrease in cardiac function (to 70%-85% of control). Further decrease in cardiac function to 50%-75% of control occurred over the next ≈ 30 minutes despite no detectable further inhibition of SERCA activity. Analysis of the 20 seconds prior to pump failure revealed a rapid decrease in end diastolic volume. Intermediate levels of SERCA function (≈ 50% of control) had only minor hemodynamic effects. Parallel experiments in field-stimulated isolated ventricular cardiomyocytes monitored intracellular Ca(2+) and cell shortening. On perfusion with thapsigargin, Ca(2+) transient amplitude and cell shortening fell to ≈ 70% of control followed by increased diastolic Ca(2+) concentration and diastolic cell shortening to achieve a new steady state. The relationship between SERCA activity and LV f...Continue Reading