Pharmacokinetic–pharmacodynamic modeling of the effect of propofol on α1-adrenoceptor-mediated positive inotropy in rat heart

Since it is unclear whether and how propofol affects the α1-mediated inotropic response, we used a pharmacokinetic–pharmacodynamic modeling approach in isolated rat hearts to analyze the effect of propofol on receptor binding and signal transduction. In Langendorff rat hearts perfused with buffer containing 12.3 μM phenylephrine, 1.27 nmol doses of [3H]-prazosin were infused (over 1 min), in the absence and presence of propofol (28 μM). Simultaneous analysis of prazosin outflow concentration and inotropic response (left ventricular developed pressure) using an agonist–antagonist interaction model allowed to estimate receptor affinity, as well as the parameters of the operational model of agonism. Propofol significantly (P < 0.05) increased the negative inotropic effect of prazosin. Modeling suggested that propofol increased the Hill coefficient, which determines the steepness of the stimulus–response curve for the positive inotropic effect of phenylephrine, from 1 to 2.6 ± 0.1 and decreased the maximum achievable inotropic effect from 121.2 ± 12 to 91.8 ± 6 mmHg. Thus, propofol may attenuate the positive inotropic effect of α1-agonists by decreasing the transduction efficiency of α1-adrenergic receptor signaling primarily at lower receptor occupancy.