Metabolism of endogenous and exogenous noradrenaline in guinea-pig atria

Summary

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.