Summary
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1.
Pairs of smooth muscles isolated from the nictitating membrane of reserpine-pretreated cats were incubated four times with 1.2 ml of Krebs' solution containing 10 ng/ml of 3H-(±)-noradrenaline for 7.5 min each (in the presence of ascorbic acid and EDTA to prevent autoxidation and of U-0521 to block COMT). The appearance of deaminated 3H-catechols in the bath was measured and regarded as a measure of neuronal uptake.
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2.
Cocaine caused a concentration-dependent inhibition of the rate of deamination; the ID50 was 5.62 μM.
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3.
Cocaine caused a concentration-dependent increase in responses of the isolated muscles to 0.059 μM (−)-noradrenaline with a maximum increase of about 115 times normal.
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4.
The results were applied to the model proposed by Maxwell et al. (1966). The agreement between the expected and observed relationship between rate of uptake and degree of supersensitivity was satisfactory. Apparently, the effect of cocaine on the nictitating membrane is predominatly or entirely prejunctional.
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5.
The results indicate that the true K m for noradrenaline and the true K i for cocaine are considerably smaller than the apparent Km and Ki values obtained with conventional methods.
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References
Berti, F., Shore, P. A.: A kinetic analysis of drugs that inhibit the adrenergic neuronal membrane amine pump. Biochem. Pharmacol. 16, 2091–2094 (1967).
Coyle, J. T., Snyder, S. H.: Catecholamine uptake by synaptosomes in homogenates of rat brain: sterospecificity in different areas. J. Pharmacol. exp. Ther. 170, 221–231 (1969).
Esterhuizen, A. C., Graham, J. D. P., Lever, J. D., Springgs, T. L. B.: Catecholamine and acetylcholinesterase distribution in relation to noradrenaline release. An enzyme histochemical and autoradiographic study on the innervation of the cat nictitating membrane. Brit. J. Pharmacol. 32, 46–56 (1968).
Finney, D. J.: Probit Analysis, 2nd ed. Cambridge: University Press 1964.
Graefe, K.-H., Eckert, E.: On the stereoselectivity of the neuronal uptake in the cat's nictating membrane. Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 45–68 (1972).
Graefe, K. H., Trendelenburg, U.: The effect of cocaine on uptake of and sensitivity to noradrenaline in isolated nictitating membranes before and after storage in the cold. Naunyn-Schmiedebergs Arch. Pharmak. 267, 383–398 (1970).
Iversen, L. L., Langer, S. Z.: Effects of phenoxybenzamine on the uptake and metabolism of noradrenaline in the rat heart and vas deferens. Brit. J. Pharmacol. 37, 627–637 (1969).
Jarrott, B.: Uptake and metabolism of catecholamines in the perfused hearts of different species. Brit. J. Pharmacol. 38, 810–821 (1970).
Kalsner, S., Nickerson, M.: Mechanism of cocaine potentiation of responses to amines. Brit. J. Pharmacol. 35, 428–439 (1969).
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. 167, 117–142 (1969).
Maxwell, R. A., Wastila, W. B., Eckhardt, S. B.: Some factors determining the response of rabbit aortic strips to dl-norepinephrine-7-H3 hydrochloride and the influence of cocaine, guanethidine and methylphenidate on these factors. J. Pharmacol. exp. Ther. 151, 253–261 (1966).
Trendelenburg, U.: Supersensitivity of the isolated nictitating membrane of the cat to sympathomimetic amines after impairment of the intraneuronal mechanisms of inactivation. Naunyn-Schmiedebergs Arch. Pharmak. 271, 29–58 (1971).
Trendelenburg, U., Höhn, D., Graefe, K. H., Pluchino, S.: The influence of block of catechol-0-methyl transferase on the sensitivity of isolated organs to catecholamines. Naunyn-Schmiedebergs Arch. Pharmak. 271, 59–92 (1971).
Trendelenburg, U., Maxwell, R. A., Pluchino, S.: Methoxamine as a tool to assess the importance of intraneuronal uptake of l-norepinephrine in the cat's nictitating membrane. J. Pharmacol. exp. Ther. 172, 91–99 (1970).
Van Orden, L. S. III, Bensch, K. G., Langer, S. Z., Trendelenburg, U.: Histochemical and fine structural aspects of the onset of denervation supersensitivity in the nictitating membrane of the spinal cat. J. Pharmacol. exp. Ther. 157, 274–283 (1967).
Varma, D. R., McCullough, H. N.: Dissociation of the supersensitivity of norepinephrine caused by cocaine from inhibition of H3-norepinephrine uptake in cold-stored smooth muscle. J. Pharmacol. exp. Ther. 166, 26–34 (1969).
Verity, M. A.: Morphologic studies of vascular neuroeffector apparatus. Proc. Symp. Physiol. Pharmacol. Vasc. Neuroeffector Systems, Interlaken 1969, pp. 2–12, Basel: Karger 1971.
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Trendelenburg, U., Graefe, K.H. & Eckert, E. The prejunctional effect of cocaine on the isolated nictitating membrane of the cat. Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 69–82 (1972). https://doi.org/10.1007/BF00505068
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DOI: https://doi.org/10.1007/BF00505068