Kenakin T P, Beek D
Department of Molecular Pharmacology, Glaxo Research Laboratories, Glaxo Inc., Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1987 Nov;243(2):482-6.
It was observed experimentally that both theophylline and isobutylmethylxanthine (IBMX) produced surmountable antagonism of the agonist effects of 2-chloroadenosine on purine receptors in rat vas deferens and guinea pig atria. In the case of IBMX, there was a statistically significant difference between the Schild regressions in the two tissues, ostensibly indicating a possible purine receptor heterogeneity with respect to the binding of this antagonist. However, the analysis was complicated by the fact that both theophylline and IBMX produced positive inotropic responses in guinea pig atria (presumably by inhibition of cardiac phosphodiesterase), making the calculation of dose ratios subjective and ambiguous. To determine whether the phosphodiesterase blocking property of theophylline and IBMX was interfering with the observation of purine receptor antagonism in guinea pig atria, a new technique described as pharmacologic resultant analysis was utilized to measure the purine receptor blocking properties of theophylline and IBMX in guinea pig atria in the presence of phosphodiesterase blockade. Based on the principle of additive dose ratios for two antagonists competing for one receptor, pharmacologic resultant analysis measures the effects of a test antagonist (in this case theophylline or IBMX) on the competitive blockade of a reference antagonist; for these studies, the reference antagonist was 8-sulfophenyltheophylline. Under these circumstances, the direct effects of the test antagonist (positive inotropy) are expressed throughout the experiment and cancel with the normal null methods used for measurement of competitive antagonism. Using this technique, it was found that the potencies of both theophylline and IBMX on the purine receptors in rat vas deferens and guinea pig atria were identical. The use of this method in the delineation of multiple drug activities is discussed.
实验观察到，茶碱和异丁基甲基黄嘌呤（IBMX）对2-氯腺苷在大鼠输精管和豚鼠心房嘌呤受体上的激动剂作用均产生可克服的拮抗作用。就IBMX而言，两种组织中的Schild回归存在统计学显著差异，表面上表明该拮抗剂结合方面可能存在嘌呤受体异质性。然而，分析变得复杂，因为茶碱和IBMX在豚鼠心房中均产生正性肌力反应（可能是通过抑制心脏磷酸二酯酶），使得剂量比的计算主观且不明确。为了确定茶碱和IBMX的磷酸二酯酶阻断特性是否干扰了豚鼠心房中嘌呤受体拮抗作用的观察，一种称为药理结果分析的新技术被用于在存在磷酸二酯酶阻断的情况下测量豚鼠心房中茶碱和IBMX的嘌呤受体阻断特性。基于两种拮抗剂竞争一个受体的加性剂量比原理，药理结果分析测量测试拮抗剂（在本案例中为茶碱或IBMX）对参考拮抗剂竞争性阻断的影响；对于这些研究，参考拮抗剂是8-磺基苯基茶碱。在这些情况下，测试拮抗剂的直接作用（正性肌力作用）在整个实验中都表现出来，并与用于测量竞争性拮抗作用的常规零方法相互抵消。使用该技术发现，茶碱和IBMX对大鼠输精管和豚鼠心房中嘌呤受体的效力是相同的。本文讨论了该方法在多种药物活性描述中的应用。
