Metabolism of endogenous and exogenous noradrenaline in guinea-pig atria
- 19 Downloads
The outflow of noradrenaline, 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxymandelic acid (DOMA) from guinea-pig isolated atria was studied by chromatography on alumina followed by high pressure liquid chromatography with electrochemical detection. In the absence of drugs, the outflow of endogenous noradrenaline over a period of 3 h averaged 1.6 pmol×g−1×min−1 and the outflow of DOPEG 17 pmol×g−1×min−1. The outflow of DOMA was below the detection limit (<0.31 pmol×g−1×min−1). Tyramine greatly increased the outflow of noradrenaline and DOPEG, and the reserpine-like compound Ro 4-1284 selectively increased the outflow of DOPEG; DOMA remained below the detection limit. When atria were exposed to (−)-noradrenaline 1.7 or 17 μM, the subsequent outflow of noradrenaline and DOPEG was enhanced. Moreover, substantial amounts of DOMA were now found. This outflow of DOMA was prevented when atria were exposed to (−)-noradrenaline in the presence of cocaine or after an initial incubation with amezinium. Exposure to (−)-noradrenaline 1.7 μM mainly enhanced the formation of DOPGE, while exposure to (+)-noradrenaline 1.7 μM mainly enhanced the formation of DOMA.
Our experiments confirm some and qualify other conclusions drawn from studies in which exogenous 3H-noradrenaline had been used to examine the metabolism of noradrenaline in guinea-pig atria. In agreement with the isotope studies, DOPEG is a major metabolite of endogenous noradrenaline. In contrast to what the isotope studies had suggested, however, endogenous DOMA is a very minor product, at least as long as the neurones are at rest. DOMA is only formed when the tissue is exposed to high concentrations of exogenous noradrenaline. In further contrast to previous conclusions, DOMA is then formed intra- and not extraneuronally.
Key wordsGuinea-pig atria High pressure liquid chromatography Noradrenaline metabolism
Unable to display preview. Download preview PDF.
- Adler-Graschinsky E, Langer SZ, Rubio MC (1972) Metabolism of norepinephrine released by phenoxybenzamine in isolated guinea-pig atria. J Pharmacol Exp Ther 180:286–301Google Scholar
- Brandão F, Monteiro JG, Osswald W (1978) Differences in the metabolic fate of noradrenaline released by electrical stimulation or by tyramine. Naunyn-Schmiedeberg's Arch Pharmacol 305:37–40Google Scholar
- Brandão F, Rodrigues-Pereira E, Monteiro JG, Osswald W (1980) Characteristics of tyramine induced release of noradrenaline: mode of action of tyramine and metabolic fate of the transmitter. Naunyn-Schmiedeberg's Arch Pharmacol 311:9–15Google Scholar
- Cubeddu L, Weiner N (1975) Release of norepinephrine and dopamine-β-hydroxylase by nerve stimulation. V. Enhanced release associated with a granular effect of a benzoquinolizine derivative with reserpine-like properties. J Pharmacol Exp Ther 193:757–774Google Scholar
- Farah MB, Adler-Graschinsky E, Langer SZ (1977) Possible physiological significance of the initial step in the catabolism of noradrenaline in the central nervous system of the rat. Naunyn-Schmiedeberg's Arch Pharmacol 297:119–131Google Scholar
- Henseling M, Trendelenburg U (1978) Stereoselectivity of the accumulation and metabolism of noradrenaline in rabbit aortic strips. Naunyn-Schmiedeberg's Arch Pharmacol 302:195–206Google Scholar
- Jonason J (1969) Metabolism of catecholamines in the central and peripheral nervous system. Acta Physiol Scand Suppl 320Google Scholar
- Langer SZ (1974) Selective metabolic pathways for noradrenaline in the peripheral and in the central nervous system. Med Biol 52:372–383Google Scholar
- Leitz FH, Stefano FJE (1971) The effect of tyramine, amphetamine and metaraminol on the metabolic disposition of 3H-norepinephrine released from the adrenergic neuron. J Pharmacol Exp Ther 178: 464–473Google Scholar
- 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 188:640–653Google Scholar
- Muldoon SM, Vanhoutte PM, Tyce GM (1978) Norepinephrine metabolism in canine saphenous vein: prevalence of glycol metabolites. Am J Physiol 234:H235-H243Google Scholar
- Rutledge CO, Weiner N (1967) The effect of reserpine upon the synthesis of norepinephrine in the isolated rabbit heart. J Pharmacol Exp Ther 157:290–302Google Scholar
- Starke K, Weitzell R (1978) Is histamine involved in the sympathomimetic effect of nicotine? Naunyn-Schmiedeberg's Arch Pharmacol 304:237–248Google Scholar
- Steppeler A, Starke K (1980) Selective inhibition by amezinium of intraneuronal monoamine oxidase. Naunyn-Schmiedeberg's Arch Pharmacol 314:13–16Google Scholar
- Steppeler A, Pfändler R, Hedler L, Starke K (1980) An analysis of the effects of amezinium on postganglionic sympathetic neurones. Naunyn-Schmiedeberg's Arch Pharmacol 314:1–11Google Scholar
- Taube HD, Starke K, Borowski E (1977) Presynaptic receptor systems on the noradrenergic neurones of rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 299:123–141Google Scholar
- Trendelenburg U, Bönisch H, Graefe KH, Henseling M (1980) The rate constants for the efflux of metabolites of catecholamines and phenethylamines. Pharmacol Rev 31:179–203Google Scholar