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 alpha(1)-mediated inotropic response, we used a pharmacokinetic-pharmacodynamic modeling approach in isolated rat hearts to analyze the effect of propofol oil receptor binding and signal transduction. In Langendorff rat hearts perfused with buffer containing 12.3 mu M phenylephrine, 1.27 nmol doses of [H-3]-prazosin were infused (over I min), in the absence and presence of propofol (28 mu M). 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 I 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 alpha(1)-agonists by decreasing the transduction efficiency of alpha(1)-adrenergic receptor signaling primarily at lower receptor occupancy. (C) 2009 Elsevier B.V. All rights reserved