1 The relation of calcium ion influx into nerve terminals to presynaptic adrenoceptor function and the possible masking, by desensitization due to intraneuronal calcium accumulation, of the effects of adrenoceptor agonists and antagonists on presynaptic alpha-adrenoceptors was investigated in guinea-pig atria previously incubated with [(3)H]-noradrenaline.2 Atria were stimulated with 100 pulses at various frequencies (1 to 15 Hz) in standard (2.3 mm), low (0.26 mm) and high (6.9 mm) calcium-Krebs solution in the absence and then the presence first of noradrenaline and subsequently phenoxybenzamine.3 The per pulse overflow of tritium was directly related to the calcium concentration of the Krebs solution, being much reduced and substantially increased in 0.26 and 6.9 mm calcium-Krebs solutions respectively.4 Noradrenaline inhibited the overflow of tritium in low calcium-Krebs solution, to a relatively constant extent, independently of frequency. In addition, the agonist had a greater maximal inhibitory effect in standard than in reduced calcium-Krebs. The catecholamine was as effective an inhibitor of overflow at the lowest and highest frequencies in high as it was in standard calcium-Krebs solution. Phenoxybenzamine invariably increased the tritium overflow but was generally less effective both in low and in high calcium-Krebs solution. The patterns of inhibition and enhancement of stimulation-induced tritium overflow by these two agents do not indicate an intimate relationship between calcium influx and adrenoceptor activation; nor does desensitization appear to be an adequate explanation of the relationship between frequency of stimulation and the intensity of agonist and antagonist effect in the three different calcium concentrations.5 It is concluded that the perineuronal levels of adrenergic transmitter do not establish the magnitudes of effect of exogenous adrenoceptor agonists and antagonists on tritium overflow and that a negative feedback regulation of release by transmitter is exceedingly unlikely under ordinary conditions of neurotransmission.