Analysis of asymmetry of agonist concentration-effect curves
Analysis of asymmetry of agonist concentration-effect curves
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DOI：
10.1016/s1056-8719(99)00026-x
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发表时间：
1999-04-01
影响因子：
1.9
通讯作者：
Schoemaker, RC
中科院分区：
文献类型：
--
作者：
Van der Graaf, PH;Schoemaker, RC
基于非线性混合效应模型和理查兹（1959，J Exp Botany 10，290-300）的原始工作，我们开发了一个拟合程序，以描述浓度-效应E/[A]曲线的不对称程度，并分析了大鼠主动脉中α（1）-肾上腺素受体激动剂获得的E/[A]曲线的形状。对于所有研究的配体，四参数理查兹模型提供了比标准logistic/Hill模型显著更好的数据拟合，这意味着E/[A]曲线是不对称的。除ST 587外，不对称参数（δ）趋向于零，并且理查兹模型可被三参数不对称Gompertz模型替代，而拟合优度无显著损失。α（1）-肾上腺素受体拮抗剂哌唑嗪（10 nM）对去甲肾上腺素EI[A]曲线的不对称性没有影响，但显著增加了拐点处的斜率。与此相反，预处理与不可逆拮抗剂，酚苄明（60 nM），产生了位移的δ估计去甲肾上腺素从零到统一，表明从不对称的变化到对称的曲线。因此，EI[A]曲线不对称性的详细统计分析表明，大鼠主动脉中的α（1）-肾上腺素受体并不作为同质的一个受体-一个换能器系统运行。通过标准logistic/Hill模型的分析或对实验数据的目视检查都无法得出该结论。总体而言，本研究中开发的曲线拟合分析提供了一种定量和灵敏的测量不对称性和一种新的方法，用于根据曲线形状客观区分激动剂作用。该方法也适用于其他药理学检测，为受体分类研究提供了一种新的工具。(C)1999 Elsevier Science Inc. All rights reserved.
We have developed a fitting procedure, based on nonlinear mixed effect modelling and original work by Richards (1959, J Exp Botany 10, 290-300), to describe the degree of asymmetry of concentration-effect E/[A] curves and analysed the shape of E/[A] curves obtained with alpha(1)-adrenoceptor agonists in rat aorta. The four-parameter Richards model provided a significantly better fit of the data than the standard logistic/Hill model for all Ligands investigated, which implies that E/[A] curves were asymmetrical. With the exception of ST 587, the asymmetry parameter (delta) tended toward zero and the Richards model could be replaced without significant loss of goodness-of-fit by the three-parameter, asymmetrical Gompertz model. The alpha(1)-adrenoceptor antagonist, prazosin (10 nM), had no effect on the asymmetry of the noradrenaline EI[A] curve but significantly increased the slope at the point of inflection. In contrast, pretreatment with the irreversible antagonist, phenoxybenzamine (60 nM), produced a shift of the delta estimate for noradrenaline from zero to unity, indicating a change from an asymmetrical to a symmetrical curve. Therefore, detailed statistical analysis of EI[A] curve asymmetry demonstrates that alpha(1)-adrenoceptors in rat aorta do not operate as a homogenous one-receptor-one-transducer system. This conclusion could not have been reached by either an analysis with the standard logistic/Hill model or visual inspection of experimental data. Overall, the curve-fitting analysis developed in this study provides a quantitative and sensitive measure of asymmetry and a novel method for the objective discrimination of agonist action on the basis of curve shape. The method is generally applicable to other pharmacological assays and provides a new tool in receptor classification studies. (C) 1999 Elsevier Science Inc. All rights reserved.