Cardiac pharmacokinetics and inotropic response of verapamil in rats with endotoxemia

The present study evaluated the effect of endotoxin-induced systemic inflammation on cardiac uptake and negative inotropic response to verapamil in isolated rat hearts. Rats received an i.p. dose of 4 mg/kg Escherichia coli lipopolysaccharide (LPS) or saline. After 5.5 h the outflow concentration-time curve and inotropic response data were measured following a 1.5 nmol dose of [(3)H]-verapamil (infused within 1 min) in Langendorff-perfused hearts and analyzed by pharmacokinetic/pharmacodynamic modeling, where the inotropic effects at individual time points were evaluated in relation to outflow concentrations at corresponding times. Endotoxemia decreased the rate of cardiac verapamil uptake and the maximal negative inotropic effect E(max) to 78% and 55%, respectively, of the values estimated in the control group (p < 0.01). The reduction in E(max) was correlated with the increase in body temperature. With verapamil as a model drug, the results give some information about potential effects of endotoxemia on the cardiac kinetics and dynamics of calcium antagonists.