Crosstalk between presynaptic angiotensin receptors, bradykinin receptors and α 2 ‐autoreceptors in sympathetic neurons: a study in α 2 ‐adrenoceptor‐deficient mice

In mouse atria, angiotensin II and bradykinin lose much or all of their noradrenaline release‐enhancing effect when presynaptic α 2 ‐autoinhibition does not operate either because of stimulation with very brief pulse trains or because of treatment with α 2 antagonists. We now studied this operational condition in α 2 ‐adrenoceptor‐deficient mice. Release of 3 H‐noradrenaline was elicited by electrical stimulation. In tissues from wild‐type (WT) mice, angiotensin II and bradykinin increased the overflow of tritium evoked by 120 pulses at 3 Hz. This enhancement did not occur or was much reduced when tissues were stimulated by 120 pulses at 3 Hz in the presence of rauwolscine and phentolamine, or when they were stimulated by 20 pulses at 50 Hz. In tissues from mice lacking the α 2A ‐adrenoceptor ( α 2A KO) or the α 2B ‐adrenoceptor ( α 2B KO), the concentration–response curves of angiotensin II and bradykinin (120 pulses at 3 Hz) were unchanged. In tissues from mice lacking the α 2C ‐adrenoceptor ( α 2C KO) or both the α 2A ‐ and the α 2C ‐adrenoceptor ( α 2AC KO), the concentration–response curves were shifted to the same extent downwards. As in WT tissues, angiotensin II and bradykinin lost most or all of their effect in α 2A KO and α 2AC KO tissues when rauwolscine and phentolamine were present or trains consisted of 20 pulses at 50 Hz. Rauwolscine and phentolamine increased tritium overflow evoked by 120 pulses at 3 Hz up to seven‐fold in WT and α 2B KO tissues, three‐fold in α 2A KO and α 2C KO tissues, and two‐fold in α 2AC KO tissues. Results confirm that angiotensin II and bradykinin require ongoing α 2 ‐autoinhibition for the full extent of their release‐enhancing effect. Specifically, they require ongoing α 2C ‐autoinhibition. The peptide effects that remain in α 2C ‐autoreceptor‐deficient mice seem to be because of α 2B ‐autoinhibition. The results hence also suggest that in addition to α 2A ‐ and α 2C ‐ mouse postganglionic sympathetic neurons possess α 2B ‐autoreceptors.British Journal of Pharmacology (2003) 138 , 1389–1402. doi: 10.1038/sj.bjp.0705223