Summary
The neuronal and extraneuronal uptake and deamination of 3H-(−)-phenylephrine was studied in perfused rat hearts obtained from reserpine-pretreated animals.
-
1.
Under the conditions of steady-state perfusion with 5 μmol/l 3H-(−)-phenylephrine slightly more than 50% of total deamination took place in adrenergic nerve endings, slightly less than 50% in the extraneuronal tissue.
-
2.
3H-(−)-phenylephrine is preferentially deaminated to the glycol metabolite.
-
3.
There is pronounced non-saturable, cocaine-and corticosterone-resistant uptake of 3H-(−)-phenylephrine in the perfused rat heart.
-
4.
The apparent rate constant for the efflux of the glycol metabolite is about 20 times higher than that for the efflux of the acid metabolite.
-
5.
For both the glycol and the acid metabolite of 3H-(−)-phenylephrine, apparent rate constants for the efflux declined when the duration of the perfusion with the labelled parent amine was prolonged. This phenomenon was also observed when the deamination of 3H-(−)-phenylephrine was restricted to either the adrenergic nerve endings or the extraneuronal tissue. These results are interpreted as evidence for a distribution of each metabolite into at least two kinetically different compartments.
-
6.
This was confirmed for the acid metabolite by determination of a biphasic efflux curve in wash-out experiments in which MAO was inhibited during washout (after an initial loading of the adrenergic nerve endings with 3H-(−)-phenylephrine).
Similar content being viewed by others
References
Adler-Graschinsky E, Langer SZ, Rubio MC (1972) Metabolism of norepinephrine released by phenoxybenzamine in isolated guinea-pig atria. J Pharmacol Exp Ther 180:286–301
Andén N-E, Roos B-E, Werdinius B (1963) On the occurrence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorometric method. Life Sci 7:448–458
Blombery P, Kopin IJ, Gordon EK, Ebert MH (1979) Metabolism and turnover of MHPG in the monkey. In: Usdin E, Kopin IJ, Barchas J (eds) Catecholamines: Basic and clinical frontiers, vol 2. Pergamon Press, New York, Oxford, pp 1875–1877
Bönisch H (1978) Further studies on the extraneuronal uptake and metabolism of isoprenaline in the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 303:121–131
Bönisch H (1980) The rate constants for the efflux of deaminated metabolites of 3H-dopamine from the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 314:231–235
Bönisch H, Trendelenburg U (1974) Extraneuronal removal, accumulation and O-methylation of isoprenaline in the perfused heart. Naunyn-Schmiedeberg's Arch Pharmacol 283:191–218
Bönisch H, Uhlig W, Trendelenburg U (1974) Analysis of the compartments involved in the extraneuronal storage and metabolism of isoprenaline in the perfused heart. Naunyn-Schmiedeberg's Arch Pharmacol 283:223–244
Bönisch H, Graefe K-H, Trendelenburg U (1978) The determination of the rate constant for the efflux of an amine from efflux curves for amine and metabolite. Naunyn-Schmiedeberg's Arch Pharmacol 304:147–155
Dubocovich ML, Langer SZ (1976) Influence of the frequency of nerve stimulation on the metabolism of 3H-norepinephrine released from the perfused cat spleen: differences observed during and after the period of stimulation. J Pharmacol Exp Ther 198:83–101
Fiebig ER, Trendelenburg U (1978a) The neuronal and extraneuronal uptake and metabolism of 3H-(−)-noradrenaline in the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 303:21–35
Fiebig ER, Trendelenburg U (1978b) The kinetic constants for the extraneuronal uptake and metabolism of 3H-(−)-noradrenaline in the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 303:37–45
Graefe K-H, Stefano FJE, Langer SZ (1973) Preferential metabolism of (−)-3H-norepinephrine through the deaminated glycol in the rat vas deferens. Biochem Pharmacol 22:1147–1160
Hellmann G, Hertting G, Peskar B (1971) Effect of pretreatment with 6-hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart. Br J Pharmacol 41:270–277
Henseling M, Trendelenburg U (1978) Stereoselectivity of the accumulation and metabolism of noradrenaline in rabbit aortic strips. Naunyn-Schmiedeberg's Arch Pharmacol 302:195–206
Henseling M, Eckert E, Trendelenburg U (1976) The distribution of 3H-(±)-noradrenaline in rabbit aortic strips after inhibition of the noradrenaline-metabolizing enzymes. Naunyn-Schmiedeberg's Arch Pharmacol 292:205–217
Henseling M, Graefe K-H, Trendelenburg U (1978) The rate constants for the efflux of the metabolites of noradrenaline from rabbit aortic strips. Naunyn-Schmiedeberg's Arch Pharmacol 302:217–215
Iversen LL (1967) The uptake and storage of noradrenaline in sympathetic nerves. Cambridge University Press, Cambridge
LaBrosse EH (1970) Catecholamine metabolism in neuroblastoma: kinetics of conversion of 3H-3-methoxy-4-hydroxyphenylglycol to 3H-3-methoxy-4-hydroxymandelic acid. J Clin Endocrinol 30:580–589
Langer SZ, Enero MA (1974) The potentiation of responses to adrenergic nerve stimulation in the presence of cocaine: its relationship to the metabolic fate of released norepinephrine. J Pharmacol Exp Ther 191:431–443
Luchelli-Fortis MA, Langer SZ (1974) Reserpine-induced depletion of the norepinephrine stores: is it a reliable criterion for the classification of the mechanism of action of sympathomimetic amines? J Pharmacol Exp Ther 188:640–653
Mack F, Bönisch H (1979) dissociation constants and lipopilicity of catecholamines and related compounds. Naunyn-Schmiedeberg's Arch Pharmacol 310:1–0
Paiva MQ, Guimaraes S (1978) A comparative study of the uptake and metabolism of noradrenaline and adrenaline by the isolated saphenous vein of the dog. Naunyn-Schmiedeberg's Arch Pharmacol 303:221–228
Paiva MQ, Osswald W (1980) Inactivation of some vasoconstrictor agonists by saphenous vein strips of the dog. J Pharm Pharmacol 32:227–228
Rawlow A, Fleig H, Kurahashi K, Trendelenburg U (1980) The neuronal and extraneuronal deamination of 3H-phenylephrine in the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 311:R61
Steppeler A (1980) Selective inhibition of intraneuronal MAO by amezinium. Naunyn-Schmiedeberg's Arch Pharmacol 311:R61
Steppeler A, Pfändler R (1979) A neurochemical study of amezinium. Naunyn-Schmiedeberg's Arch Pharmacol 308:R13
Thoenen H, Hürlimann A, Haefely W (1968) Mechanism of amphetamine accumulation in the isolated perfused heart of the rat. J Pharm Pharmacol 20:1–11
Trendelenburg U, Muskus A, Fleming WW, Gomez Alonso de la Sierra B (1962) Effect of cocaine, denervation and decentralization on the response of the nictitating membrane to various sympathomimetic amines. J Pharmacol Exp Ther 138:181–193
Trendelenburg U, Bönisch H, Graefe K-H, Henseling M (1979) The rate constants for the efflux of metabolites of catecholamines and phenethylamines. Pharmacol Rev 31:179–203
Winkler H, Smith AD (1972) Phaeochromocytoma and other catecholamine-producing tumours. In: Blaschko H, Muscholl E (eds) Catecholamines, Handbook Exp. Pharmacol., vol. XXXIII, Springer-Verlag, Berlin Heidelberg New York, pp 900–933
Author information
Authors and Affiliations
Additional information
This study was supported by the Deutsche Forschungsgemeinschaft (Tr 96). Some of the results were communicated to the German Pharmacological Society (Rqwlow et al. 1980)
A. Rawlow was a fellow of the Deutscher Akademischer Austauchdienst and K. Kurahashi of the Humboldt-Foundation
Rights and permissions
About this article
Cite this article
Rawlow, A., Fleig, H., Kurahashi, K. et al. The neuronal and extraneuronal uptake and deamination of 3H-(−)-phenylephrine in the perfused rat heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 314, 237–247 (1980). https://doi.org/10.1007/BF00498545
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00498545