Errors in the measurement of agonist potency-ratios produced by uptake processes: a general model applied to beta-adrenoceptor agonists

British Journal of Pharmacology
T P Kenakin

Abstract

1. The sensitization of guinea-pig atria and trachea to noradrenaline, isoprenaline, and salbutamol, produced by an inhibitor of neuronal (cocaine) and extraneuronal (metanephrine) uptake, was studied quantitatively. The data were compared to a theoretical model. 2. Cocaine produced near maximal sensitization to noradrenaline in guinea-pig atria (5 fold) at concentrations which produced only partial sensitization in guinea-pig trachea (4.7 fold sensitization of a maximum 11 fold). These results agreed with the model which predicts that there is a direct relationship between the amount of uptake inhibitor required to produce full sensitization and the magnitude of maximal sensitization demonstrable in the tissue. This makes extrapolation of uptake inhibition concentrations from tissue to tissue a potentially erroneous practice. 3. In normal trachea, salbutamol is 20 times more potent than noradrenaline but this difference is abolished (to 0.9 times) by cocaine (100 microM). This reduction of potency-ratio is due to the selective cocaine-induced sensitization of trachea to noradrenaline and raises a serious objection to the classification of salbutamol as a beta 2 selective agonist. 4. Metanephrine produced very little sensitizat...Continue Reading

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Citations

Dec 1, 1983·Naunyn-Schmiedeberg's Archives of Pharmacology·T ShojiT Shigei
Sep 1, 1982·Naunyn-Schmiedeberg's Archives of Pharmacology·J J Cole, S R O'Donnell
Jan 15, 1985·European Journal of Pharmacology·P G Duncan, J S Douglas
Nov 22, 1988·European Journal of Pharmacology·L B FernandesR G Goldie
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Jul 1, 1985·Journal of Pharmacological Methods·T P Kenakin
May 1, 1983·British Journal of Pharmacology·R G GoldieJ L Wale
Jul 17, 2004·Autonomic & Autacoid Pharmacology·A L Al-Motarreb, K J Broadley
Nov 1, 1986·British Journal of Pharmacology·J W BlackN P Shankley
Oct 1, 1982·British Journal of Pharmacology·J A Leedham, J N Pennefather
Apr 1, 1984·British Journal of Pharmacology·S R O'Donnell, J C Wanstall

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