Crosstalk between presynaptic angiotensin receptors, bradykinin receptors and α₂‐autoreceptors in sympathetic neurons: a study in α₂‐adrenoceptor‐deficient mice

Abstract

1 In mouse atria, angiotensin II and bradykinin lose much or all of their noradrenaline release-enhancing effect when presynaptic a 2 -autoinhibition does not operate either because of stimulation with very brief pulse trains or because of treatment with a 2 antagonists. We now studied this operational condition in a 2 -adrenoceptor-deficient mice. Release of 3 H-noradrenaline was elicited by electrical stimulation. 2 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. 3 In tissues from mice lacking the a 2A -adrenoceptor (a 2A KO) or the a 2B -adrenoceptor (a 2B KO), the concentration -response curves of angiotensin II and bradykinin (120 pulses at 3 Hz) were unchanged. In tissues from mice lacking the a 2C -adrenoceptor (a 2C KO) or both the a 2A -and the a 2C -adrenoceptor (a 2AC KO), the concentration -response curves were shifted to the same extent downwards. 4 As in WT tissues, angiotensin II and bradykinin lost most or all of their effect in a 2A KO and a 2AC KO tissues when rauwolscine and phentolamine were present or trains consisted of 20 pulses at 50 Hz. 5 Rauwolscine and phentolamine increased tritium overflow evoked by 120 pulses at 3 Hz up to seven-fold in WT and a 2B KO tissues, three-fold in a 2A KO and a 2C KO tissues, and two-fold in a 2AC KO tissues. 6 Results confirm that angiotensin II and bradykinin require ongoing a 2 -autoinhibition for the full extent of their release-enhancing effect. Specifically, they require ongoing a 2C -autoinhibition. The peptide effects that remain in a 2C -autoreceptor-deficient mice seem to be because of a 2B -autoinhibition. The results hence also suggest that in addition to a 2A -and a 2C -mouse postganglionic sympathetic neurons possess a 2B -autoreceptors.

Angiotensin AT1 – α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats

“…It has been shown that on-going α 2 AR-signaling markedly enhanced the stimulating effect of the angiotensin AT1 receptor (AT 1 R) – phospholipase C – protein kinase C (PKC) pathway on norepinephrine release in the rat vas deferens (Talaia et al, 2006). Similarly, studies on tissues from genetically modified mice (Trendelenburg et al, 2003a) demonstrated that the enhancing effect of release-stimulating receptors, including the AT 1 R, depended on active α 2 AR-signaling. However, the interaction involved the α 2C AR-subtype only (Figure 1).…”

“…AT 1 R-G q -signaling stimulates norepinephrine release by interfering with the down-stream signaling of G i (Cox et al, 2000). The AT 1 R/α 2 AR interaction involved only the α 2C - and not the α 2A -subtype (Trendelenburg et al, 2003a). The present results show that α 2C AR-stimulation or AT 1 R-inhibition was required for α 2A AR to effectively moderate peripheral norepinephrine release in SHR during tyramine-stimulated norepinephrine release.…”

Functional evidence that in the cardiovascular system AT angiotensin II receptors are AT prejunctionally and AT postjunctionally

“…Thus, and since the evidence supporting the view that there are AT 1A and AT 1B subtypes with pharmacological expression rely on differences between pre-and postjunctional AT 1 receptors, the comparison of the receptors mediating the prejunctional facilitation of noradrenaline with those mediating the postjunctional effect of angiotensin II will constitute the nuclear message of this review. The facilitation of noradrenaline release caused by angiotensin II -which is apparently mediated by AT 1B -receptors -requires an ongoing a 2 -autoinhibition (some degree of tonic autoinhibition) since the blockade of a 2 -autoreceptors prevents the effect of angiotensin II [12,13].…”

Differential contributions of alpha-1 and alpha-2 adrenoceptors to vasoconstriction in mesenteric arteries and veins of normal and hypertensive mice

“…It is known that α-ARs could interact with other receptor systems in ways that are receptor-specific. For example, in mouse atria, angiotensin and bradykinin receptors interact with α 2 -AR (Cox et al, 2000;Trendelenburg et al, 2003) and protein kinase C activation plays a role in this functional interaction (Mota and Guimaraes, 2003). More detailed experiments are necessary to determine whether or not there is direct coupling of α 1 -and α 2 -ARs or if post receptor events are responsible for the functional interaction in veins.…”