Inhibition by dopamine of the stimulation-induced efflux of [3H]noradrenaline in renal arteries: limitations of the unitary hypothesis of presynaptic regulation of transmitter release.

The supposition was tested that a pattern of agonist inhibition of 3H-labelled transmitter efflux which shows a decline in intensity as the frequency of stimulation rises provides major evidence for the existence of a functional autoinhibitory feedback loop mediated by released transmitter and located on adrenergic nerve terminals. For these experiments dopamine was used, as it is not released in significant quantities in the ordinary course of sympathetic nerve activation and it appears to act presynaptically in several tested tissues at a locus discrete from that acted on by noradrenaline. Dopamine (3 X 10(-7) and 3 X 10(-6) M) inhibited the stimulation-induced efflux of [3H]noradrenaline from cattle renal arteries and did so to a declining extent with increasing frequency (1-15 Hz). Known antagonists of dopamine action, pimozide and metoclopromide, antagonized this effect of dopamine but did not by themselves enhance stimulation-induced transmitter efflux or block the inhibiting effects of exogenous noradrenaline on efflux, establishing the specificity of dopamine action in renal artery and indicating the absence of an operative negative feedback loop mediated by dopamine. This interpretation was substantiated by the finding that although dopamine reduced the magnitude of contractile responses to nerve stimulation neither pimozide nor metoclopromide enhanced the amplitude of nerve-induced contractions. It thus appears that a pattern of agonist effect on transmitter efflux which manifests a diminution in intensity as the frequency of stimulation climbs is not derived from the operation of an ongoing autoinhibitory feedback system regulating transmitter release but by a yet to be established factor.