5-HT<sub>4</sub> receptors in nucleus tractus solitarii attenuate  cardiopulmonary reflex in anesthetized rats

Edwards, Emma; Paton, Julian F. R.

doi:10.1152/ajpheart.1999.277.5.h1914

Cited by 15 publications

(14 citation statements)

References 26 publications

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“…We also investigated a possible role for AC inhibition (reduced cAMP) in these neurochemical and BP responses because activation of GPR18, a Gi/o-coupled receptor, reduces cAMP in vitro (McHugh et al, 2010) and activation of the a 2 -adrenergic receptor, another Gi/o-coupled receptor, enhances brainstem ERK1/2 and nNOS phosphorylation and lowers BP (Zhang and Abdel-Rahman, 2005;Nassar and AbdelRahman, 2008). Because cAMP measurement in the scarce RVLM tissue was not feasible, we tested our hypothesis by microinjecting forskolin to generate cAMP (Edwards and Paton, 1999). We show that intra-RVLM inhibition of PI3K/Akt (wortmannin) or ERK1/2 (PD98059) or cAMP elevation (forskolin) virtually abolished the hypotension (Figs.…”

Section: Discussionmentioning

confidence: 96%

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Penumarti

Abdel‐Rahman

2014

The Journal of Pharmacology and Experimental Therapeutics

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Direct activation of the endocannabinoid receptor G protein-coupled receptor 18 (GPR18) in the rostral ventrolateral medulla (RVLM) of conscious rats by abnormal cannabidiol (Abn CBD; trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) elevates local nitric oxide (NO) and adiponectin (ADN) levels and reduces oxidative stress and blood pressure (BP). However, the molecular mechanisms for GPR18-mediated neurochemical responses, including the nitric oxide synthase isoform that generates NO, and their potential causal link to the BP reduction are not known. We hypothesized that GPR18-mediated enhancement of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and neuronal nitric oxide synthase (nNOS) phosphorylation, triggered by a reduction in cAMP, accounts for the NO/ADN-dependent reductions in RVLM oxidative stress and BP. Intra-RVLM GPR18 activation (Abn CBD; 0.4 mg) enhanced RVLM Akt, ERK1/2, and nNOS phosphorylation as well as ADN levels during the hypotensive response. Prior GPR18 blockade with O-1918 (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]benzene) produced the opposite effects and abrogated Abn CBD-evoked neurochemical and BP responses. Pharmacological inhibition of RVLM phosphoinositide 3-kinase (PI3K)/Akt (wortmannin), ERK1/2 (PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one]), or nNOS (N v -propyl-Larginine), or activation of adenylyl cyclase (forskolin) virtually abolished intra-RVLM Abn CBD-evoked hypotension and the increases in Akt, ERK1/2, and nNOS phosphorylation and in ADN levels in the RVLM. Our pharmacological and neurochemical findings support a pivotal role for PI3K, Akt, ERK1/2, nNOS, and adenylyl cyclase, via modulation of NO, ADN, and cAMP levels, in GPR18 regulation of the RVLM redox state and BP in conscious rats.

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Section: Discussionmentioning

confidence: 96%

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Penumarti

Abdel‐Rahman

2014

The Journal of Pharmacology and Experimental Therapeutics

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“…As yet, we have no explanation for this unexpected non-Mendelian ratio. A cardiovascular or respiratory problem may have occurred (Edwards and Paton, 1999;Eftekhari et al, 2001;Manzke et al, 2003). Despite this bias, the mice lacking 5-HT 4 receptors appeared to develop normally.…”

Section: Generation Of 5-ht 4 Receptor-null Micementioning

confidence: 99%

Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT₄Receptor Knock-Out Mice

Compan¹,

Zhou²,

Grailhe³

et al. 2004

J. Neurosci.

157

111

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To study the functions of 5-HT 4 receptors, a null mutation was engineered in the corresponding gene. 5-HT 4 receptor knock-out mice displayed normal feeding and motor behaviors in baseline conditions but abnormal feeding and locomotor behavior in response to stress and novelty. Specifically, stress-induced hypophagia and novelty-induced exploratory activity were attenuated in the knock-out mice. In addition, pentylenetetrazol-induced convulsive responses were enhanced in the knock-out mice, suggesting an increase in neuronal network excitability. These results provide the first example of a genetic deficit that disrupts the ability of stress to reduce feeding and body weight and suggest that 5-HT 4 receptors may be involved in stress-induced anorexia and seizure susceptibility.

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“…This effect is specific of the activation of 5-HT 3 receptors, because it can be blocked by prior intra-NTS administration of 5-HT 3 receptor antagonists, but it remains unchanged after local administration of antagonists acting at other receptor types [127]. Interestingly, in both anaesthetized and awake rats, stimulation of 5-HT 3 receptors in the NTS also inhibits the cardiac component of the Bezold-Jarisch reflex [47,104,185]. Moreover, the bradycardic component of the carotid chemoreflex, but not the sympathoexcitatory component of this reflex, can as well be inhibited by bilateral microinjections of 5-HT 3 receptor agonists into the NTS [18,183].…”

Section: Cardiovascular Effects Of Intra-nts Microinjection Of 5-ht Amentioning

confidence: 97%

“…Numerous pharmacological, electrophysiological and immunohistochemical studies provided evidence of the existence of 5-HT 1 [38,83,120,154,216], 5-HT 2 [78,126,155,189,190,216], 5-HT 3 [62,127,160,184,185,216] and 5-HT 4 [47] receptors in the NTS. Analysis of the effects, in anaesthetized rats, of iontophoretically applied 5-HT receptor agonists onto NTS neurons receiving vagal afferent inputs showed that 5-HT 1 and 5-HT 2 receptor stimulation can either excite or inhibit this neuronal population [189,216].…”

Section: Serotoninmentioning

confidence: 99%

The Key Role of Medullary 5-HT3 Receptors in the Serotonin-Mediated Neural Control of Cardiovascular Function

Sévoz‐Couche¹,

Machado²,

Hamon³

et al. 2005

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The baroreceptor reflex plays a crucial role in the homeostatic control of cardiovascular parameters. In the central nervous system, the nucleus of the tractus solitarius (NTS) is critically involved in cardiovascular reflex control because it is both the first site of termination of glutamatergic baroreceptor afferent fibres and an important integrative area for the sensory afferent signals reaching the brainstem. In addition to glutamate, the NTS contains numerous neurotransmitters that could participate in the modulations of the baroreceptor reflex sensitivity which occur under various physiological conditions. In particular, a large body of evidence indicates that serotonin plays a modulatory role in the central control of blood pressure, especially at the level of the NTS, which is innervated by both central and peripheral serotonergic fibres. Indeed, serotonin exerts multiple cardiovascular influences through the activation of several receptors in the NTS. Actually, the NTS is the central area endowed with the highest density of serotonin 3 (5-HT 3 ) receptors whose stimulation triggers all the adaptive cardiovascular changes normally associated with behavioural responses to various stressful conditions.In this review, we first assess the current knowledge about the mechanisms underlying the cardiovascular effects of the specific activation of serotonergic receptors in the NTS. Secondly, we describe evidence that, in the NTS, 5-HT 3 receptors play a key role in one of the crucial homeostatic responses that characterise the defence reaction: the inhibitory modulation of the parasympathetic cardiac component of the baroreceptor reflex. The possible functional interactions of 5-HT 3 receptors with GABA A , NK 1 and NMDA receptors within the NTS are also discussed.

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5-HT₄ receptors in nucleus tractus solitarii attenuate cardiopulmonary reflex in anesthetized rats

Cited by 15 publications

References 26 publications

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT₄Receptor Knock-Out Mice

The Key Role of Medullary 5-HT3 Receptors in the Serotonin-Mediated Neural Control of Cardiovascular Function

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5-HT4 receptors in nucleus tractus solitarii attenuate cardiopulmonary reflex in anesthetized rats

Cited by 15 publications

References 26 publications

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT4Receptor Knock-Out Mice

The Key Role of Medullary 5-HT3 Receptors in the Serotonin-Mediated Neural Control of Cardiovascular Function

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5-HT₄ receptors in nucleus tractus solitarii attenuate cardiopulmonary reflex in anesthetized rats

Attenuated Response to Stress and Novelty and Hypersensitivity to Seizures in 5-HT₄Receptor Knock-Out Mice