Summary
An equation is derived from a mathematical model (proposed by Furchgott) which, under certain circumstances, estimates the pK I (-log dissociation constant) of a competitive inhibitor of agonist uptake by utilizing the sensitization of isolated tissues, to the substrate-agonist, by uptake inhibition. The method is theoretically more sound and appears to be improved by the use of potency-ratios of the substrate-agonist and an agonist which is not a substrate for the uptake process since this allows for the detection and correction of receptor and toxic effects of uptake inhibitors. The pK I values of cocaine, desmethylimipramine and imipramine for the neuronal uptake of norepinephrine were estimated by this method in guinea-pig tracheae and left atria. Also, the pK I values for 17 β-oestradiol, corticosterone, clonidine and metanephrine for the extraneuronal uptake of isoproterenol were estimated in guinea-pig tracheae (and cat left atria for 17 β-oestradiol). All estimates were consistent with literature pK I values obtained biochemically with radiolabelled substrates.
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References
Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58
Blinks JR (1965) Convenient apparatus for recording contractions of isolated heart muscle. J Appl Physiol 20:755–757
Brimijoin S, Pluchino S, Trendelenburg U (1970) On the mechanism of supersensitivity of norepinephrine in the denervated cat spleen. J Pharmacol Exp Ther 175:503–513
Burgen ASV, Iversen LL (1965) The inhibition of noradrenaline uptake by sympathetic amines in the rat isolated heart. Br J Pharmacol 25:34–49
Drew GM, Hildich A, Levy GP (1978) Effect of labetalol on the uptake of [3H]-(−)-noradrenaline into the isolated vas deferens of the rat. Br J Pharmacol 63:471–474
Ebner F, Waud DR (1978) The role of uptake of noradrenaline for its positive inotropic effect in relation to muscle geometry. Naunyn-Schmiedeberg's Arch Pharmacol 303:1–6
Foster RW (1967) The potentiation of the responses to noradrenaline and isoprenaline in guinea-pig isolated tracheal chain preparation by desipramine, cocaine, phentolamine, phenoxybenzamine, guanethidine, metanephrine and cooling. Br J Pharmacol 31:466–482
Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muscholl E (eds) Handbuch der experimentellen Pharmakologie, vol 33, Catecholamines. Springer, Berlin Heidelberg New York, p 283
Green AL (1976) The kinetics of enzyme action and inhibition in intact tissues and tissue slices, with special reference to cholinesterase. J Pharm Pharmacol 28:265–274
Guimarães S, Paiva MQ (1977) Differential influence of block of catechol-O-methyl transferase (COMT) activity and of neuronal uptake on α- and β-adrenergic effects. J Pharm Pharmacol 29:502–503
Hughes IE (1978) The stability of noradrenaline in physiological saline solutions. J Pharm Pharmacol 30:124–126
Iversen LL (1965) Inhibition of noradrenaline uptake by drugs. J Pharm Pharmacol 17:62–64
Iversen LL (1973) Neuronal and extraneuronal uptake mechanisms. In: Usdin E, Snyder SH (eds) Frontiers in catecholamine reseach. Proc. 3rd Ints. catecholamine symp. Pergamon Press New York, p 403
Kenakin TP (1980a) Errors in the measurement of agonist potency-ratios produced by uptake processes: A general model applied to betaadrenoceptor agonists. Br J Pharmacol 71:407–417
Kenakin TP (1980b) On the importance of agonist concentrationgradients within isolated tissues. Increased maximal responses of rat vasa deferentia to 1-norepinephrine after blockade of neuronal uptake. J Pharm Pharmacol 32:833–838
Langer SZ, Trendelenburg U (1969) 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 167:117–142
Langer SZ, Rubio MC (1973) Effects of noradrenaline metabolites on the adrenergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 276:71–88
Salt PJ (1972) Inhibition of noradrenaline uptake in the isolated rat heart by steroids, clonidine and methoxylated phenylethylamines. Eur J Pharmacol 20:329–340
Trendelenburg U (1963) Supersensitivity and subsensitivity to sympathomimetic amines. Pharmacol Rev 15:225–276
Trendelenburg U (1968) The effect of cocaine on the pacemaker of isolated guinea-pig atria. J Pharmacol Exp Ther 161:22–31
Trendelenburg U (1972) Factors influencing the concentration of catecholamines at the receptors. In: Blaschko H, Muscholl E (eds) Handbuch der experimentellen Pharmakologie, vol 33, Catecholamines. Springer, Berlin Heidelberg New York, p 726
Waud DR (1969) A quantitative model for the effect of a saturable uptake on the slope of the dose-response curve. J Pharmacol Exp Ther 167:140–141
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Kenakin, T.P. A pharmacological method to estimate the pK I of competitive inhibitors of agonist uptake processes in isolated tissues. Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 89–95 (1981). https://doi.org/10.1007/BF00505300
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DOI: https://doi.org/10.1007/BF00505300