title: Errors in the measurement of agonist potency-ratios produced by uptake processes: a general model applied to beta-adrenoceptor agonists.
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 sensitization of trachea to isoprenaline. Experiments with salbutamol showed metanephrine to be a simple competitive antagonist of beta-adrenoceptors (pKb = 4.3) and that this receptor antagonism masked sensitization to isoprenaline. 5. A theoretical model indicates that an inhibitor of agonist uptake requires a remarkable degree of selectivity for the uptake mechanism (i.e. Kb for receptors 10(4) x KI for uptake sites) to demonstrate tissue sensitization to the agonist. This analysis and the data with metanephrine indicate that a sinistral shift of the concentration-response curve is a poor indicator of the importance of uptake mechanisms in an isolated tissue. 6. An alternate method to determine the importance of agonist-uptake effects on concentration-response curves is described which utilizes agonist potency ratios. Agonist potency ratios in guinea-pig atria and trachea showed that the bronchoselectivity demonstrated by salbutamol (with respect to isoprenaline) is reduced from 54 to 7.8 by metanephrine reflecting the importance of extraneuronal uptake in trachea.
mesh_terms: D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008676:Metanephrine / Q000494:pharmacology; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D008676:Metanephrine; D003042:Cocaine; D000420:Albuterol; D009638:Norepinephrine