Enhancement of noradrenaline release by angiotensin II and bradykinin in mouse atria: evidence for cross‐talk between G q/11 protein‐ and G i/o protein‐coupled receptors

The interaction between α 2 ‐autoreceptors and receptors for angiotensin (AT 1 ) and bradykinin (B 2 ) was studied in mouse isolated atria. The preparations were labelled with [ 3 H]‐noradrenaline and then superfused with desipramine‐containing medium and stimulated electrically. Angiotensin II (10 −11 –10 −7   M ), angiotensin III (10 −10 –10 −6   M ) and bradykinin (10 −11 –10 −7   M ) enhanced the evoked overflow of tritium when preparations were stimulated with conditions that led to marked α 2 ‐autoinhibition (120 pulses at 3 Hz), but not when stimulated with conditions that led to little α 2 ‐autoinhibition (20 pulses at 50 Hz). Blockade of α‐adrenoceptors by phentolamine (1 or 10 μ M ) reduced or abolished the effect of angiotensin II and bradykinin on the overflow response to 120 pulses at 3 Hz. Addition of the δ‐opioid agonist [ D ‐Ser 2 ]‐leucine enkephalin‐Thr (DSLET, 0.1 μ M ), or of neuropeptide Y (0.1 μ M ), together with phentolamine, restored the effect of angiotensin II and bradykinin. The β‐adrenoceptor agonist terbutaline (10 −9 –10 −4   M ) enhanced the evoked overflow of tritium irrespective of the degree of autoinhibition. The experiments show that (i) a marked prejunctional facilitatory effect of angiotensin and bradykinin in mouse isolated atria requires prejunctional α 2 ‐autoinhibition; (ii) in the absence of α 2 ‐autoinhibition, activation of other prejunctional G i/o protein‐coupled reeptors, namely opioid and neuropeptide Y receptors, restores a marked effect of angiotensin II and bradykinin; and (iii) the facilitatory effect of terbutaline is not dependent upon the degree of α 2 ‐autoinhibition. The findings indicate that the major part of the release‐enhancing effect elicited through prejunctional G q/11 protein‐coupled receptors is due to disruption of an ongoing, α 2 ‐autoreceptor‐triggered G i/o protein mediated inhibition.British Journal of Pharmacology (2000) 129 , 1095–1102; doi: 10.1038/sj.bjp.0703167