Angiotensin peptides as neurotransmitters/neuromodulators in the dorsomedial medulla

1. The present review provides an update on evidence of the neurotransmitter pathways and location of receptors within the nucleus tractus solitarii (NTS) mediating the baroreflex and other haemodynamic actions of angiotensin (Ang) II. 2. A series of studies suggests a significant role for substance P in the acute cardiovascular and carotid sinus chemoreceptor facilitatory actions of AngII in the NTS. The use of antisense oligonucleotides to AT1 receptors indicates both pre- and post-synaptic AngII receptors are likely to be involved in these actions. 3. With respect to baroreceptor reflex actions, it is clear that endogenous AngII impairs the gain for operation of the baroreceptor reflex, because AT1 receptor antagonists facilitate reflex function. This effect is either independent of substance P or involves inhibition of release. Moreover, initial data obtained using antisense oligonucleotides to AT1 receptors suggest that, in the NTS, the effect of endogenous AngII on the baroreceptor reflex is mainly due to presynaptic actions on vagal or carotid sinus afferent fibres. In contrast, the level of endogenous AngII within the NTS appears to have variable effects on activation of cardiopulmonary vagal afferent fibres by phenylbiguanide. These results indicate a divergence of effects of AngII on reflexes evoked by these two different types of sensory input. 4. Use of transgenic rats with alterations in brain angiotensin peptides allowed us to assess the effect of long-term alterations in brain Ang peptides on reflex function. We studied (mRen2)27 transgenic rats (TGR(mRen2)) with high brain medulla AngII levels and transgenic rats with angiotensinogen (Aogen) antisense linked to glial fibrillary acidic protein promoter (TGR(ASrAogen)) with greatly reduced brain Aogen. The reflex evoked by activation of cardiac vagal chemosensitive afferent fibres was enhanced in TGR(ASrAogen), whereas the baroreceptor reflex control of heart rate was attenuated in TGR(mRen2), further confirming a divergence of effects of AngII on these two sensory modalities. 5. The overall results are consistent with a sustained inhibitory effect of AngII on the baroreceptor reflexes, with dose-dependent or activation-dependent effects on cardiac vagal afferent fibre activation. Moreover, alterations in substance P pathways may contribute to the actions of AngII on reflex function.