Only piperoxan (10 ,iM) slightly enhanced the overflow at 10 pulses, 2 Hz. The effects of yohimbine and piperoxan were similar in arteries not exposed to cocaine and in those that were perfused/superfused with medium containing cocaine (10 riM) after preincubation. 4 It is concluded that yohimbine, phentolamine and piperoxan increase the release of noradrenaline only when the concentration of noradrenaline in the biophase of the ear artery is sufficiently high. The effect is, hence, an anti-noradrenaline effect and due to the blockade of presynaptic x-adrenoceptors. A second prerequisite for the release-enhancing effect appears to be a sufficient length of the pulse train, indicating that the o-adrenergic auto-inhibition develops relatively slowly.

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The outflow of noradrenaline, 3, 4-dihydroxy-phenylglycol (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 x g-1 x min-1 and the outflow of DOPEG 17 pmol x g-1 x min-1. The outflow of DOMA was below the detection limit (less than 0.31 pmol x g-1 x min-1). Tyramine greatly increased the outflow of noradrenaline and DOPEG, and the reserpine-like compound Ro4-1284 selectively increased the outflow of DOPEG; DOMA remained below the detection limit. When atria were exposed to (-) noradrenaline 1.7 or 17 microM, 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 microM mainly enhanced the formation of DOPEG, while exposure to (+)-noradrenaline 1.7 microM 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.

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