Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1980;71(2):407–417. doi: 10.1111/j.1476-5381.1980.tb10953.x

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

T P Kenakin
PMCID: PMC2044440  PMID: 6110457

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.

Full text

PDF
407

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blinks J. R. Convenient apparatus for recording contractions of isolated heart muscle. J Appl Physiol. 1965 Jul;20(4):755–757. doi: 10.1152/jappl.1965.20.4.755. [DOI] [PubMed] [Google Scholar]
  3. Brimijoin S., Pluchino S., Trendelenburg U. On the mechanism of supersensitivity to norepinephrine in the denervated cat spleen. J Pharmacol Exp Ther. 1970 Nov;175(2):503–513. [PubMed] [Google Scholar]
  4. Bönisch H., Trendelenburg U. Extraneuronal removal, accumulation and O-methylation of isoprenaline in the perfused heart. Naunyn Schmiedebergs Arch Pharmacol. 1974;283(2):191–218. doi: 10.1007/BF00501145. [DOI] [PubMed] [Google Scholar]
  5. Ebner F., Waud D. R. The role of uptake of noradrenaline of its positive inotropic effect in relation to muscle geometry. Statistical evaluation. Naunyn Schmiedebergs Arch Pharmacol. 1978 May;303(1):1–6. doi: 10.1007/BF00496179. [DOI] [PubMed] [Google Scholar]
  6. Foster R. W. An uptake of radioactivity from (plus or minus)-3H-isoprenaline and its inhibition by drugs which potentiate the responses to (minus)-isoprenaline in the guinea-pig isolated trachea. Br J Pharmacol. 1969 Mar;35(3):418–427. doi: 10.1111/j.1476-5381.1969.tb08283.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Foster R. W. The potentiation of the responses to noradrenaline and isoprenaline of the guinea-pig isolated tracheal chain preparation by desipramine, cocaine, phentolamine, phenoxybenzamine, guanethidine, metanephrine and cooling. Br J Pharmacol Chemother. 1967 Nov;31(3):466–482. doi: 10.1111/j.1476-5381.1967.tb00412.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Geddes B. A., Jones T. R., Dvorsky R. J., Lefcoe N. M. Interaction of glucocorticoids and bronchodilators on isolated guinea pig tracheal and human bronchial smooth muscle. Am Rev Respir Dis. 1974 Oct;110(4):420–427. doi: 10.1164/arrd.1974.110.4.420. [DOI] [PubMed] [Google Scholar]
  9. Guimarães S., Paiva M. Q. Differential influence of block of catechol-O-methyl transferase (COMT) activity and of neuronal uptake on alpha- and beta-adrenergic effects. J Pharm Pharmacol. 1977 Aug;29(8):502–503. doi: 10.1111/j.2042-7158.1977.tb11379.x. [DOI] [PubMed] [Google Scholar]
  10. Kenakin T. P., Black J. W. The pharmacological classification of practolol and chloropractolol. Mol Pharmacol. 1978 Jul;14(4):607–623. [PubMed] [Google Scholar]
  11. Lands A. M., Arnold A., McAuliff J. P., Luduena F. P., Brown T. G., Jr Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967 May 6;214(5088):597–598. doi: 10.1038/214597a0. [DOI] [PubMed] [Google Scholar]
  12. Lands A. M., Luduena F. P., Buzzo H. J. Adrenotrophic beta-receptors in the frog and chicken. Life Sci. 1969 Apr 1;8(7):373–382. doi: 10.1016/0024-3205(69)90230-6. [DOI] [PubMed] [Google Scholar]
  13. Langer S. Z., Trendelenburg U. The effect of a saturable uptake mechanism on the slopes of dose-response curves for sympathomimetic amines and on the shifts of dose-response curves produced by a competitive antagonist. J Pharmacol Exp Ther. 1969 May;167(1):117–142. [PubMed] [Google Scholar]
  14. O'Donnell S. R., Wanstall J. C. The contribution of extraneuronal uptake to the trachea-blood vessel selectivity of beta-adrenoceptor stimulants in vitro in guinea-pigs. Br J Pharmacol. 1976 Jul;57(3):369–373. doi: 10.1111/j.1476-5381.1976.tb07675.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Trendelenburg U. The effect of cocaine on the pacemaker of isolated guinea-pig atria. J Pharmacol Exp Ther. 1968 Jun;161(2):222–231. [PubMed] [Google Scholar]
  16. VAN ROSSUM J. M. Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther. 1963;143:299–330. [PubMed] [Google Scholar]
  17. Wöppel W., Trendelenburg U. Temperature-dependent supersensitivity of isolated atria to catecholamines. Eur J Pharmacol. 1973 Sep;23(3):302–305. doi: 10.1016/0014-2999(73)90100-3. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES