Viscerosensory input drives angiotensin II type 1A receptor expressing neurons in the solitary tract nucleus (original) (raw)
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American journal of physiology. Regulatory, integrative and comparative physiology, 2017
Angiotensin II acts via two main receptors within the CNS, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme, tyrosine hydroxylase (TH) and a sub-population of these stained for the transcription factor Phox2b. A third group, comprising approximately two thirds of the AT1AR-expressing NTS neurons showed Phox 2b-immunoreactivity alone. A fourt...
Cardiovascular role of angiotensin type1A receptors in the nucleus of the solitary tract of mice
Cardiovascular Research, 2013
Bilateral microinjections of lentivirus expressing AT 1A receptors (AT 1A v mice, n ¼ 6) or green fluorescent protein (GFPv, n ¼ 8, control) under the control of the PRSx8 promotor were made into the NTS of AT 1A receptors null mice (AT 1A 2/2 ). Telemetry devices recorded blood pressure (BP), heart rate (HR), and locomotor activity. Expression of AT 1A receptors in the NTS increased BP by 11.2 + 4 mmHg (P , 0.05) at 2 and 3 weeks, whereas GFPv mice remained at pre-injection BP. Ganglion blockade reduced BP to similar levels pre-and post-transfection in GFPv and AT 1A v mice.
AJP: Regulatory, Integrative and Comparative Physiology, 2007
Circulating ANG II modulates the baroreceptor reflex control of heart rate (HR), at least partly via activation of ANG II type 1 (AT1) receptors on neurons in the area postrema. In this study, we tested the hypothesis that the effects of circulating ANG II on the baroreflex also depend on AT1 receptors within the nucleus tractus solitarius (NTS). In confirmation of previous studies in other species, increases in arterial pressure induced by intravenous infusion of ANG II had little effect on HR in urethane-anesthetized rats, in contrast to the marked bradycardia evoked by equipressor infusion of phenylephrine. In the presence of a continuous background infusion of ANG II, the baroreflex control of HR was shifted to higher levels of HR but had little effect on the baroreflex control of renal sympathetic activity. The modulatory effects of circulating ANG II on the cardiac baroreflex were significantly reduced by microinjection of candesartan, an AT1 receptor antagonist, into the area...
Brain Research, 2013
Although anatomical data indicates that the caudal ventrolateral medulla (CVLM) projects directly to the subfornical organ (SFO), little is known about the afferent information relayed through the CVLM to SFO. Experiments were done in the anesthetized rat to investigate whether CVLM neurons mediate baroreceptor afferent information to SFO and whether this afferent information alters the response of SFO neurons to systemic injections of angiotensin II (ANG II). Extracellular single unit recordings were made from 78 spontaneously discharging single units in SFO. Of these, 32 (41%) responded to microinjection of L-glutamate (L-Glu; 0.25 M; 10 nl) into CVLM (27/32 were inhibited and 5/32 were excited). All 32 units also were excited by systemic injections of ANG II (250 ng/ 0.1 ml, ia). However, only those units inhibited by CVLM (n ¼27) were found to be inhibited by the reflex activation of baroreceptors following systemic injections of phenylephrine (2 mg/kg, iv). Activation of CVLM or arterial baroreceptors in conjunction with ANG II resulted in an attenuation of the SFO unit's response to ANG II. Finally, microinjections (100 nl) of the synaptic blocker CoCl 2 or the non-specific glutamate receptor antagonist kynurenic acid into CVLM attenuated (10/13 units tested) the SFO neuron's response to activation of baroreceptors, but not the unit's response evoked by systemic ANG II. Taken together, these data suggest that baroreceptor afferent information relayed through CVLM functions to modulate of the activity of neurons within SFO to extracellular signals of body fluid balance.
American Journal of Physiology-Heart and Circulatory Physiology, 2010
The novel peptide, angiotensin (ANG)-(1–12), elicits a systemic pressor response and vasoconstriction. These effects are blocked by ANG converting enzyme (ACE) inhibitors or AT1 receptor antagonists, suggesting a role as an ANG II precursor. However, ANG-(1–12) can serve as a substrate for either ANG II or ANG-(1–7) formation, depending on the local tissue enzymes. Although levels of ANG-(1–12) are higher than ANG I or ANG II in brain, the role and processing of this peptide for autonomic control of heart rate (HR) has yet to be considered. Thus we examined the effects of nucleus tractus solitarii (NTS) microinjection of ANG-(1–12) on baroreflex sensitivity for control of HR, resting arterial pressure (AP) and HR, and indexes of sympathovagal balance in urethane/chloralose anesthetized Sprague-Dawley rats. NTS injection of ANG-(1–12) (144 fmol/120 nl) significantly impaired the evoked baroreflex sensitivity to increases in AP [ n = 7; 1.06 ± 0.06 baseline vs. 0.44 ± 0.07 ms/mmHg aft...
Angiotensin receptors and actions in guinea pig enteric nervous system
AJP: Gastrointestinal and Liver Physiology, 2005
Actions of ANG II on electrical and synaptic behavior of enteric neurons in the guinea pig small intestine were studied. Exposure to ANG II depolarized the membrane potential and elevated neuronal excitability. The number of responding neurons was small, with responses to ANG II in 32% of submucosal neurons and 25% of myenteric neurons. Hyperpolarizing responses were evoked by ANG II in 45% of the neurons. The hyperpolarizing responses were suppressed by α2-noradrenergic receptor antagonists, which suggested that the hyperpolarizing responses reflected stimulation of norepinephrine release from sympathetic neurons. Exposure to ANG II enhanced the amplitude and prolonged the duration of noradrenergic inhibitory postsynaptic potentials and suppressed the amplitude of both fast and slow excitatory postsynaptic potentials. The selective ANG II1 receptor (AT1R) antagonists, ZD-7115 and losartan, but not a selective AT2R antagonist (PD-123319), suppressed the actions of ANG II. Western bl...
European Journal of Pain, 2013
The angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. Methods: We used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence. Results: AT2R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1R antagonist losartan had no effect on capsaicin responses. AT2R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/ medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas. Conclusions: AT2R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.
Tzu Chi Medical Journal, 2007
Many homeostatic reflexes depend on autonomic central nervous system mechanisms to systemically coordinate visceral organ function. The nucleus of the solitary tract (NTS) is the common entry of cranial visceral afferents into these regulatory pathways. Such NTS neurons initiate adjustments in cardiovascular, respiratory, gastrointestinal and other visceral systems. Diversity of neurons within the NTS appears integral to such pro cessing but is daunting to approach experimentally. This review outlines three experimental approaches to understanding cellular heterogeneity within NTS and its relation to function. Brainstem slice preparations coupled with patch recordings afford cellular-molecular resolution with substantial links to the more intact system. Pharmacological approaches based on visceral afferent phenotype have helped identify myelinated and unmyelinated solitary tract inputs to NTS neurons. An interesting outcome has been the robust association of A-type potassium currents with NTS neurons receiving unmyelinated afferents. Neuroanatomical tracers offer a second, complementary approach. Anterograde transport of fluorescent dye identifies cranial visceral afferent terminals on second order neurons that cluster on or proximal to the soma-a highly unusual distribution in the central nervous system. Thus, second order baroreceptive neurons can be identified neuroanatomically in vitro. Equally helpful has been identification of NTS projection neurons by retrograde tracers injected into target regions of the hypothalamus or brainstem and this approach indicates substantial specialization-relative homogeneous neurons within the overall heterogeneity of NTS. Lastly, transgenic mouse strains, particularly those expressing marker chromophores, have identified phenotypic subtypes such as GABAergic inhibitory neurons within NTS. Combined methodologies are forging new understanding of NTS and autonomic regulation.
Journal of Neurochemistry, 2019
Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type-2 receptor for Angiotensin-II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type-1 receptor for Angiotensin-II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT-PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation-induced neuritogenesis. We demonstrated that AT2R-neurons express C-or A-neuron markers, primarily IB4, trkA and substance-P. AT1R expression was highest in small neurons and co-localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA while AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted cooperatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non-peptidergic C-neurons neuritogenesis while AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous-induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain.