Experimental Testing of Mackay's Model for Functional Antagonism in the Isolated Costo-uterus of the Rat

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 1985 Sep 1

PMID 3840396

Citations 3

Authors

P J Henry

K M Lulich

J W Paterson

Affiliations

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Abstract

Several key predictions of a recently developed model for functional antagonism (Mackay, 1981) were experimentally tested using the rat isolated costo-uterine preparation. In the presence of the functional antagonist fenoterol (Fen), the functional constants (KAF) for carbachol and oxotremorine (Oxo) were respectively 9.9 and 3.4 fold greater than their corresponding affinity constants (KA). According to Mackay's model for functional antagonism, the higher KAF/KA ratio for carbachol indicates that this cholinoceptor agonist has a greater efficacy than Oxo. This was confirmed by using conventional pharmacological methods. As predicted from the model of functional antagonism, the plot of KAF/KA-1 against the fraction of cholinoceptors not irreversibly blocked by phenoxybenzamine (Pbz) was linear for both carbachol and Oxo and the lines of best fit crossed the axes at a point not significantly different from the origin. The value of 4.6 for the relative efficacy of carbachol to Oxo estimated from functional antagonism studies was comparable to the value of 5.6 calculated using the method of irreversible antagonism proposed by Furchgott (1966).

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References

FURCHGOTT R . Pharmacological characterization of receptors: its relation to radioligand-binding studies. Fed Proc. 1978; 37(2):115-20. View

Delean A, Munson P, Rodbard D . Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978; 235(2):E97-102. DOI: 10.1152/ajpendo.1978.235.2.E97. View

Takeyasu K, Uchida S, Wada A, Maruno M, Lai R, Hata F . Experimental evidence and dynamic aspects of spare receptor. Life Sci. 1979; 25(20):1761-71. DOI: 10.1016/0024-3205(79)90480-6. View

Mackay D . An analysis of functional antagonism and synergism. Br J Pharmacol. 1981; 73(1):127-34. PMC: 2071862. DOI: 10.1111/j.1476-5381.1981.tb16781.x. View

Emmerson J, Mackay D . A test of the null equation for functional antagonism. Br J Pharmacol. 1981; 73(1):135-41. PMC: 2071831. DOI: 10.1111/j.1476-5381.1981.tb16782.x. View

Amidon G, Buckner C . A theoretical model for the use of functional antagonism to estimate dissociation constants for agonists. J Pharmacol Methods. 1982; 7(2):173-8. DOI: 10.1016/0160-5402(82)90030-4. View

van den Brink F, Offermeier J, Griessel H . Sensitization of contracted tracheal smooth muscle to beta-adrenergic spasmolysis by subthreshold doses of papaverine. Scand J Respir Dis Suppl. 1977; 98:47-50. View

Ringdahl B . Determination of dissociation constants and relative efficacies of oxotremorine analogs at muscarinic receptors in the guinea-pig ileum by pharmacological procedures. J Pharmacol Exp Ther. 1984; 229(1):199-206. View

McPherson G, Molenaar P, RAPER C, Malta E . Analysis of dose-response curves and calculation of agonist dissociation constants using a weighted nonlinear curve fitting program. J Pharmacol Methods. 1983; 10(4):231-41. DOI: 10.1016/0160-5402(83)90017-7. View

10.

van den Brink F . The model of functional interaction. I. Development and first check of a new model of functional synergism and antagonism. Eur J Pharmacol. 1973; 22(3):270-8. DOI: 10.1016/0014-2999(73)90026-5. View

11.

van den Brink F . The model of functional interaction. II. Experimental verification of a new model: the antagonism of beta-adrenoceptor stimulants and other agonists. Eur J Pharmacol. 1973; 22(3):279-86. DOI: 10.1016/0014-2999(73)90027-7. View

12.

Ohashi M . Studies on the mode of antagonism between adrenergic beta-mimetics and beta-blocking agents (III). Functional antagonism between beta-mimetics and spasmogens. Jpn J Pharmacol. 1976; 26(3):315-23. DOI: 10.1254/jjp.26.315. View

13.

Ringdahl B, JENDEN D . Pharmacological properties of oxotremorine and its analogs. Life Sci. 1983; 32(21):2401-13. DOI: 10.1016/0024-3205(83)90365-x. View