The adenosine receptor‐mediated inhibition of noradrenaline release possibly involves a N‐protein and is increased by α2‐autoreceptor blockade

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Abstract
The stimulation‐evoked overflow of [3H]‐noradrenaline from slices of the rabbit hippocampus is inhibited by α2‐autoreceptors as well as by adenosine (A1)‐receptors. Slices of rabbit hippocampus were labelled with [3H]‐noradrenaline, superfused continuously and stimulated twice electrically (rectangular pulses; 2 ms, 3 Hz, 24 mA, 5 V cm−1). Treatment of hippocampal slices with N‐ethylmaleimide (NEM, 30 μm; 30 min), which functionally disturbs certain N‐proteins, decreased the inhibitory action of adenosine receptor agonists like (‐)‐N6‐(R‐phenylisopropyl)‐adenosine ((‐)‐PIA) and adenosine on noradrenaline release. Release inhibition caused by (‐)‐PIA (0.03‐1 μm) was antagonized by NEM in a non‐competitive manner in the absence and in the presence of the α2‐adrenoceptor antagonist yohimbine. The adenosine receptor antagonist 8‐phenyltheophylline significantly increased the evoked noradrenaline release by about 15% in control slices by diminishing the inhibitory action of endogenous adenosine. In NEM‐treated slices this effect of 8‐phenytheophylline was not seen. In the presence of (‐)‐PIA (0.1 μm), i.e. under conditions of an increased inhibitory tone, release facilitation by 8‐phenyltheophylline was decreased by NEM compared to that in the respective controls. Occupation of the A1‐receptor with (‐)‐PIA prior to and during the NEM treatment did not protect the A1‐receptor‐coupled signal transduction system from being affected by NEM. In the presence of the α2‐adrenoceptor antagonist yohimbine, the inhibitory action of (‐)‐PIA was strongly increased. The above results suggest the involvement of a regulatory N‐protein in the A1‐receptor‐mediated inhibition of noradrenaline release and an interaction between the α2‐autoreceptor and the A1‐receptor‐coupled signal transduction system, possibly at the level of a N‐protein.