Kenakin T P
J Pharm Pharmacol. 1980 Dec;32(12):833-8. doi: 10.1111/j.2042-7158.1980.tb13086.x.
It is assumed often that blockade of agonist uptake processes in isolated tissues results only in shifts to the left of the concentration-response curves to the agonist with no concomitant increase in the maximal response. This may not be true in tissues where diffusion is not fast enough to permit penetration of the agonist to a sufficient number of muscle cells for production of tissue maximal response. Under these circumstances an agonist-concentration gradient is created within the tissue which, when altered, could lead to an increase in the maximal response to the agonist. The increased maximal responses of rat visa deferentia to (--)-noradrenaline after blockade of neuronal uptake by either cocaine or desmethylimipramine have been analysed in terms of a concentration-gradient hypothesis. The data are compared with a theoretical calculation based on a model of restricted diffusion of enzyme-substrates into structured tissues. Both the experimental data and theoretical calculations suggest that an altered concentration-gradient of (--)-noradrenaline within the muscle layers of rat vasa deferentia is responsible for the increased maximal response. The effects of such gradients are discussed in terms of quantitation of drug-receptor phenomena and as a caveat to ascribing increases in maximal responses to post-synaptic effects of uptake inhibitors.
人们常常认为，在离体组织中阻断激动剂摄取过程只会导致激动剂浓度-反应曲线向左移动，而最大反应不会随之增加。在那些扩散速度不够快，不足以使激动剂渗透到足够数量的肌肉细胞以产生组织最大反应的组织中，情况可能并非如此。在这种情况下，组织内会形成激动剂浓度梯度，当该梯度发生改变时，可能会导致对激动剂的最大反应增加。已根据浓度梯度假说分析了可卡因或去甲丙咪嗪阻断神经元摄取后大鼠输精管对（-）-去甲肾上腺素的最大反应增加的情况。将这些数据与基于酶底物在结构化组织中受限扩散模型的理论计算进行了比较。实验数据和理论计算均表明，大鼠输精管肌层内（-）-去甲肾上腺素浓度梯度的改变是最大反应增加的原因。从药物-受体现象的定量角度以及将最大反应增加归因于摄取抑制剂的突触后效应的注意事项方面讨论了这种梯度的影响。
