Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Eur J Pharm Sci. 2009 Nov 5;38(4):389-94. doi: 10.1016/j.ejps.2009.09.006. Epub 2009 Sep 16.
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 on receptor binding and signal transduction. In Langendorff rat hearts perfused with buffer containing 12.3 microM phenylephrine, 1.27 nmol doses of [(3)H]-prazosin were infused (over 1 min), in the absence and presence of propofol (28 microM). 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 alpha(1)-agonists by decreasing the transduction efficiency of alpha(1)-adrenergic receptor signaling primarily at lower receptor occupancy.
由于目前尚不清楚丙泊酚是否以及如何影响 alpha(1)介导的变力反应，我们使用了一种在分离的大鼠心脏中进行的药代动力学-药效学建模方法来分析丙泊酚对受体结合和信号转导的影响。在使用含有 12.3 microM 苯肾上腺素的缓冲液灌注的 Langendorff 大鼠心脏中，在不存在和存在丙泊酚（28 microM）的情况下，输注 1.27 nmol 剂量的 [(3)H]-哌唑嗪（在 1 分钟内）。使用激动剂-拮抗剂相互作用模型同时分析哌唑嗪流出浓度和变力反应（左心室发展压力），可以估计受体亲和力以及激动作用操作模型的参数。丙泊酚显着（P<0.05）增加了哌唑嗪的负性变力作用。建模表明，丙泊酚增加了决定苯肾上腺素正性变力作用的刺激-反应曲线陡度的 Hill 系数，从 1 增加到 2.6+/-0.1，并使最大可实现的变力作用从 121.2+/-12 降低至 91.8+/-6 mmHg。因此，丙泊酚可能通过降低 alpha(1)肾上腺素能受体信号转导的效率，尤其是在较低的受体占有率下，减弱 alpha(1)激动剂的正性变力作用。
