PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

Farnham, Melissa M.J.; Li, Qun; Goodchild, Ann K.; Pilowsky, Paul M.

doi:10.1152/ajpregu.00753.2007

Cited by 67 publications

(100 citation statements)

References 39 publications

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“…Both peptides are present in nerve terminals that surround SPN, and both peptides exert potent cardiovascular effects elsewhere in the brain but have no effect on blood pressure or reflexes on their own in the spinal cord (9,12,13). A key difference, however, is that catestatin delivered intrathecally does not affect MAP, HR, sSNA, or adaptive reflexes (12).…”

Section: Discussionmentioning

confidence: 99%

“…Catestatin is contained within 88% of C1 RVLM neurons, and PACAP-38 is expressed in 85% of bulbospinal C1 RVLM neurons, indicating extensive colocalization of these neurotransmitters in this nucleus (9, 13). The separate effects of these peptides have been studied following injection into the intrathecal space and into the RVLM, (9,12,49,50), but the physiological significance of this extensive colocalization is unclear.Catestatin and PACAP are both vasodilator peptides in the periphery (11,54). Intrathecal PACAP increases splanchnic sympathetic nerve activity (sSNA) and heart rate (HR) but does not affect mean arterial blood pressure (MAP) (9).…”

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confidence: 99%

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confidence: 99%

“…Two vesicular peptides of interest in the current study are catestatin (human chromogranin A 352-372 ), a vasoactive chromogranin A (CgA) cleavage product (32), and pituitary adenylate cyclase-activating polypeptide (PACAP) (39). Catestatin is contained within 88% of C1 RVLM neurons, and PACAP-38 is expressed in 85% of bulbospinal C1 RVLM neurons, indicating extensive colocalization of these neurotransmitters in this nucleus (9,13). The separate effects of these peptides have been studied following injection into the intrathecal space and into the RVLM, (9,12,49,50), but the physiological significance of this extensive colocalization is unclear.…”

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confidence: 99%

“…Intrathecal PACAP increases splanchnic sympathetic nerve activity (sSNA) and heart rate (HR) but does not affect mean arterial blood pressure (MAP) (9). Intrathecal catestatin on its own has no effect on MAP, sSNA, or HR; however, it is pressor and sympathoexcitatory in the RVLM and significantly enhances the sympathetic baroreflex, although it blunts the hypoxic chemoreflex and somatosympathetic reflexes (13).…”

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Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

Gaede

Inglott

Farnham

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Gaede AH, Inglott MA, Farnham MM, Pilowsky PM. Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure. Am J Physiol Regul Integr Comp Physiol 303: R719 -R726, 2012. First published August 8, 2012 doi:10.1152/ajpregu.00202.2012.-This study focuses on presympathetic neurons of the rostral ventrolateral medulla (RVLM) that regulate sympathetic vasomotor tone. Many neurotransmitters are colocalized in RVLM neurons and are released under specific conditions to modulate efferent homeostatic responses. Of particular interest here are two peptides colocalized in catecholaminergic RVLM neurons: catestatin and pituitary adenylate cyclase-activating polypeptide (PACAP). Chromogranin A-derived catestatin is a potent endogenous noncompetitive nicotinic and adrenoreceptor antagonist. Catestatin impairs adenylate cyclase and phospholipase C action: mechanisms engaged by PACAP. Although PACAP and catestatin are likely coreleased, the possible effects of this are unknown. We aimed to determine whether catestatin affects the normal sympathoexcitatory but isotensive responses to intrathecal PACAP. Urethane-anesthetized, vagotomized, ventilated Sprague-Dawley rats (n ϭ 22) were given an intrathecal injection of catestatin at different times prior to intrathecal administration of PACAP-38. Arterial pressure, splanchnic sympathetic nerve activity, heart rate, and reflex responses to baroreceptor and chemoreceptor activation were recorded. The key findings of this study are that pretreatment with catestatin time dependently enhances the PACAP-38 effect on mean arterial pressure and enhances sympathetic barosensitivity and chemosensitivity. The timescale of the effect of catestatin on the response to PACAP-38 strongly suggests that catestatin is either causing changes in gene expression to exert its effects, or modifying intracellular mechanisms normally engaged by PAC 1 receptors. The ability of catestatin pretreatment to enhance barosensitivity and chemosensitivity after PACAP-38 injection supports the hypothesis that catestatin manipulates the intracellular environment within sympathetic neurons in a way that increases responses to PACAP. chromogranin a; sympathetic; baroreflex; chemoreflex; epinephrine HYPERTENSION IS A MAJOR HUMAN health problem that is due, in large part, to increased sympathetic drive that emanates from the rostral ventrolateral medulla (RVLM) (42,44,45). Central neural mechanisms maintain arterial blood pressure by integrating information from reflexes and central behavioral and emotional states to alter efferent sympathetic and parasympathetic activity, according to need (18,44,45). The RVLM plays a critical role in this system as the final integrative pathway in the regulation of sympathetic tone and cardiovascular adaptive reflexes (e.g., the baroreceptor and chemoreceptor reflexes) (45). The RVLM contains a functionally heterogeneous cell population that includes barosensitive, presympathetic (C1) neurons, which project to sympathetic preganglionic neu...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

Gaede

Inglott

Farnham

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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The orexinergic neurons receive synaptic input from C1 cells in rats

Bochorishvili

Nguyen

Coates

et al. 2014

J of Comparative Neurology

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The C1 cells, located in the rostral ventrolateral medulla (RVLM), are activated by pain, hypoxia, hypoglycemia, infection and hypotension and elicit cardiorespiratory stimulation, adrenaline and ACTH release, and arousal. The orexin neurons contribute to the autonomic responses to acute psychological stress. Here, using an anatomical approach, we consider whether the orexin neurons could also be contributing to the autonomic effects elicited by C1 neuron activation. Phenylethanolamine N-methyl transferase-immunoreactive (PNMT-ir) axons were detected amongst orexin-ir somata and close appositions between PNMT-ir axonal varicosities and orexin-ir profiles were observed. The existence of synapses between PNMT-ir boutons labeled with diaminobenzidine and orexinergic neurons labeled with immunogold was confirmed by electron microscopy. We labeled RVLM neurons with a lentiviral vector that expresses the fusion protein ChR2-mCherry under the control of the catecholaminergic neuron-selective promoter PRSx8 and obtained light and ultrastructural evidence that these neurons innervate the orexin cells. Using a Cre-dependent adeno-associated vector and TH-Cre rats we confirmed that the projection from RVLM catecholaminergic neurons to the orexinergic neurons originates predominantly from PNMT-ir catecholaminergic (i.e. C1 cells). The C1 neurons were found to establish predominantly asymmetric synapses with orexin-ir cell bodies or dendrites. These synapses were packed with small clear vesicles and also contained dense core vesicles. In summary, the orexin neurons are among the hypothalamic neurons contacted and presumably excited by the C1 cells. The C1-orexin neuronal connection is probably one of several suprabulbar pathways through which the C1 neurons activate breathing and the circulation, raise blood glucose and facilitate arousal from sleep.

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Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

Parker

Shen

Wearne

et al. 2017

J of Comparative Neurology

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Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed.

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PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

Cited by 67 publications

References 39 publications

Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

The orexinergic neurons receive synaptic input from C1 cells in rats

Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

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