On the importance of agonist concentration-gradients within isolated tissues. Increased maximal responses of rat vasa deferentia to (–)-noradrenaline after blockade of neuronal uptake

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Abstract
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 vasa deferentia to (–)-noradrenaline after blockade of neuronal uptake by either cocaine or desmethylimi-pramine 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 enzymesubstrates 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.