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Lack of correlation between presynaptic inhibition of noradrenaline release and end organ responses during nerve
Abstract:
1 LD 3098 (cirazoline) is an imidazoline derivative, possessing agonist properties at alpha-adrenoceptor sites.2 When transmitter release was measured directly as tritium overflow from perfused cat spleen preparations, prelabelled with [(3)H]-noradrenaline, LD 3098 was found to be 10 times more selective for presynaptic than for postsynaptic alpha-adrenoceptors.3 In addition, in this preparation, LD 3098 appears to induce a postsynaptic sensitization to the transmitter released by nerve depolarization because under conditions in which [(3)H]-noradrenaline overflow decreased, there was a paradoxical potentiation in the response to nerve stimulation. This potentiation also occurred with a concentration of LD 3098 that did not per se affect stimulation-evoked [(3)H]-noradrenaline release or the basal perfusion pressure of the spleen.4 Both the reduction in (3)H-transmitter release induced through activation of alpha-presynaptic adrenoceptors and the potentiation of the responses to nerve stimulation were concentration-dependent phenomena.5 In pentobarbitone anaesthetized dogs, the heart rate response to low frequency ansa-subclavia stimulation was not affected by LD 3098. Whilst the alpha(1) mediated increase in blood pressure responses to injected noradrenaline and tyramine was significantly potentiated by LD 3098, the beta(1)-mediated heart rate responses to these injected amines were not modified in the presence of LD 3098.6 Thus it is possible that the failure to detect any presynaptic effects with LD 3098 when transmitter release is measured indirectly at the level of the postsynaptic responses is due to end organ sensitivity changes.7 These findings emphasize that caution is necessary when assessing presynaptic alpha-adrenoceptor effects through end organ responses to nerve stimulation both in vitro and in vivo and the need for measurements of transmitter overflow as well as adequate postsynaptic controls in such experiments.