Mechanism-based modeling of reduced inotropic responsiveness to digoxin in endotoxemic rat hearts

The mechanisms by which endotoxemia affects myocardial contractility and responsiveness to inotropic drugs are not well understood. We examined the positive inotropic effect of digoxin in single-pass Langendorff-perfused hearts from rats after in vivo pretreatment with lipopolysaccharide (LPS, 4 mg/kg, i.p., 4 h before heart isolation). Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding and effectuation kinetics after three consecutive digoxin doses (15, 30, and 45 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange (NCX) inhibitor KB-R7943 (0.1 microM) in perfusate. LPS significantly depressed baseline contractility and the inotropic response to digoxin without affecting its uptake mechanism. Compared with the control group, the slope of the functional receptor occupancy (stimulus)-to-response relationship was reduced by 44% in the LPS group. Model analysis revealed a significant correlation between changes in digoxin action and LPS-induced febrile response: digoxin receptor affinity increased and the response/stimulus ratio decreased with rise in body temperature, respectively. In contrast, the diminished responsiveness to digoxin observed after NCX inhibition in the control group was not further attenuated in the LPS group. These results support the hypothesis that postreceptor events may be responsible for the diminished contractile response to digoxin during endotoxemia.