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Ketanserin is a selective 5-hydroxytryptamine (serotonin)-2A receptor (5-HT2AR) antagonist. Studies have suggested that ketanserin exerts anti-inflammatory effects independent of the baroreflex; however, the mechanisms involved remain unclear. Thus, in the present study, we aimed to evaluate the effects of ketanserin in colitis and the possible underlying mechanisms. The expression of 5-HT2AR was assessed in the colon tissues of patients with inflammatory bowel disease (IBD) and in mice with dextran sodium sulfate (DSS)-induced colitis. The therapeutic potential of ketanserin was investigated in the mice with colitis. In the colon tissue samples from the patients with IBD, a high expression level of 5-HT2AR was observed. Treatment with ketanserin attenuated the progression of experimental colitis in the mice, as indicated by body weight assessment, colon length, histological scores and cytokine release. The colonic macrophages from the ketanserin-treated mice with colitis exhibited a decreased production of inflammatory cytokines, with M2 polarization and impaired migration. The knockdown of 5-HT2AR using siRNA partly abolished the inhibitory effects of ketanserin on the release of pro-inflammatory cytokines in bone marrow derived-macrophages (BMDMs), thus demonstrating that the inhibitory effects of ketanserin on the production of inflammatory cytokines are partly dependent on 5-HT2AR. Ketanserin also inhibited the activation of nuclear factor-κB (NF-κB) in BMDMs. In conclusion, the findings of the present study demonstrate that ketanserin alleviates colitis. Its anti-inflammatory effects may be due to the promotion of the anti-inflammatory function of macrophages through 5-HT2AR/NF-κB.
Liver fibrosis is problematic after persistent injury. However, little is known about its response to an acute insult. Accumulation of myeloid lineage cells contributes into the promotion and resolution of inflammation and fibrosis. Using Cre-transgenic mice that specifically mark myeloid lineage cells with EYFP and burn as a model of acute systemic injury, we investigated the role of myeloid lineage cells in the liver after acute injury. Our data show that thermal injury in mice (30% total body surface area) induces fibrosis predominantly around portal venules whereas myeloid cells are enriched throughout the liver. The fibrosis peaks around 1-2 weeks post injury and resolves by week 3. Ablating myeloid cells led to lower fibrosis. Through FACS sorting, we isolated myeloid lineage cells (EYFP +ve cells) from injured animals and from the control uninjured animals and subjected the extracted RNA from these cells to microarray analysis. Microarray analysis revealed an inflammatory signature for EYFP +ve cells isolated from injured animals in comparison with control cells. Moreover, it showed modulation of components of the serotonin (5-HT) pathway in myeloid cells. Antagonizing the 5HT2A/2C receptor decreased fibrosis in thermally injured mice by skewing macrophages away from their pro-fibrotic phenotype. Macrophages conditioned with Ketanserin showed a lower pro-fibrotic phenotype in a co-culture system with mesenchymal cells. There is a spatiotemporal pattern in liver fibrosis post-thermal injury, which is associated with the influx of myeloid cells. Treating mice with a 5HT2A/2C receptor antagonist promotes an anti-fibrotic effect, through modulating the phenotype of macrophages.
5-HT(2A) receptor antagonists improve antidepressant responses when added to 5-HT-selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5-hydroxytryptaminergic system in the antidepressant-like effect of this combined treatment, given subchronically.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant drugs. The addition of low dose of 5-hydroxytryptamine type 2A enhances the therapeutic effect of SSRIs. The purpose of the present studies was to test the effects of combined treatment of a low dose of ketanserin (KET) and escitalopram (ESC) on behavioral anomalies occurring after olfactory bulbectomy (OBX).
Prepulse inhibition (PPI) of the acoustic startle response is an operational measure of sensorimotor gating that can be assessed in animals and in humans. Serotonin releasers such as MDMA disrupt PPI and reduce startle habituation in rodents. These effects are prevented by pretreatment with selective serotonin uptake inhibitors, indicating that the effect of MDMA on startle plasticity is largely due to carrier-mediated release of serotonin from presynaptic terminals. In contrast, MDMA has been shown to increase PPI in humans. It is unclear, however, whether the MDMA-induced increase in PPI in humans is also dependent on carrier-mediated serotonin release and which postsynaptic receptors are involved. We investigated the effects of three different pretreatments on the MDMA-induced effects on PPI and habituation in humans. Pretreatments were: (1) the highly selective serotonin uptake inhibitor citalopram (40 mg IV) in 16 subjects, (2) the D(2) antagonist haloperidol (1.4 mg IV) in 14 subjects, and (3) the 5-HT(2A/C) antagonist ketanserin (50 mg PO) in 14 subjects. Each of the three studies used a double-blind placebo-controlled design. All healthy volunteers were examined four times at 2-4-week intervals after placebo, pretreatment, MDMA (1.5 mg/kg PO), and pretreatment plus MDMA. MDMA increased PPI. Habituation was not altered by MDMA, although MDMA-induced individual differences on habituation and psychological symptoms were inversely correlated. Citalopram attenuated the MDMA-induced increase in PPI and most of the psychological effects of MDMA. Neither haloperidol nor ketanserin had any effect on PPI increases produced by MDMA, although each partially attenuated some MDMA-induced psychological effects. Results are consistent with the view that MDMA increases PPI of the acoustic startle reflex in humans via release of presynaptic serotonin.
1. The aim of this study was to characterize the 5-HT receptors involved in the 5-HT-induced contraction of longitudinal muscle (LM) strips of porcine proximal stomach. This was done in a classical organ bath set-up for isotonic measurement. 2. The concentration-contraction curve to 5-HT was not modified by 5-HT(3) and 5-HT(4) receptor antagonism. Methysergide, ketanserin and mesulergine antagonized the curve to 5-HT. Concomitantly, increasing concentrations of ketanserin and mesulergine progressively revealed a biphasic nature of the 5-HT curve. Ketanserin antagonized the low-affinity receptor while it did not modify the high-affinity receptor. 3. Tetrodotoxin did not influence the concentration-contraction curve to 5-HT neither in the absence nor presence of ketanserin, indicating that nerves are not involved. 4. Ketanserin competitively antagonized the monophasic concentration-response curve to alpha-Methyl-5-HT, yielding a Schild slope that was not significantly different from unity. After constraining the Schild slope to unity, a pK(B) estimate of 8.23+/-0.90 was obtained. This affinity estimate of ketanserin closely approximates previously reported affinities at 5-HT(2A) receptors. 5. In the presence of ketanserin (0.1 microM; exposing the high-affinity receptor), a wide range of 5-HT receptor antagonists covering all 5-HT receptors known, was tested. Only methysergide and ritanserin inhibited the response to 5-HT, thus expressing affinity for the high-affinity receptor. This did not reveal the identity of the receptor involved. 6 It can be concluded that 5-HT induces pig proximal stomach (LM) contraction via 5-HT(2A) receptors located on smooth muscle. A ketanserin-insensitive phase of contractions could not be characterized between the actually known classes of 5-HT receptors with the pharmacological tools that were used.
Rhythmic animal behaviors are regulated in part by neural circuits called the central pattern generators (CPGs). Classifying neural population activities correlated with body movements and identifying the associated component neurons are critical steps in understanding CPGs. Previous methods that classify neural dynamics obtained by dimension reduction algorithms often require manual optimization which could be laborious and preparation-specific. Here, we present a simpler and more flexible method that is based on the pre-trained convolutional neural network model VGG-16 and unsupervised learning, and successfully classifies the fictive motor patterns in Drosophila larvae under various imaging conditions. We also used voxel-wise correlation mapping to identify neurons associated with motor patterns. By applying these methods to neurons targeted by 5-HT2A-GAL4, which we generated by the CRISPR/Cas9-system, we identified two classes of interneurons, termed Seta and Leta, which are specifically active during backward but not forward fictive locomotion. Optogenetic activation of Seta and Leta neurons increased backward locomotion. Conversely, thermogenetic inhibition of 5-HT2A-GAL4 neurons or application of a 5-HT2 antagonist decreased backward locomotion induced by noxious light stimuli. This study establishes an accelerated pipeline for activity profiling and cell identification in larval Drosophila and implicates the serotonergic system in the modulation of backward locomotion.
The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more "anxious" phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or had no effect (CLF).
Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT(2A) receptor (5-HT(2A)R) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT(2A)R. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT(2A)R density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [³H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [³H]ketanserin binding sites to the 5-HT(2A)R was increased in antipsychotic-free (128 ± 11%), but not in antipsychotic-treated (92 ± 12%), schizophrenic subjects. In suicide victims, [³H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [³H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [³H]ketanserin binding to the 5-HT(2A)R was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [³H]ketanserin binding to the 5-HT(2A)R in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT(2A)R is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.
1. The mechanisms by which histamine and 5-HT differentially contract pulmonary arteries and veins are unclear. In lung explants from 26 guinea-pigs, we compared responses of pulmonary arteries and vein to histamine, 5-HT and KCI, and examined potential determinants for the differential responses. Lungs were filled with agarose, sectioned into approximately 1 mm thick slices, and vascular luminal areas measured by image analysis. 2. Histamine and 5-HT produced a concentration-dependent constriction in arteries and veins, greater in the latter. KCl constricted arteries and veins equally. 3. The histamine H1 antagonist chlorpheniramine (10(-4) M) abolished contractions to histamine; the H2 antagonist cimetidine enhanced maximal responses and sensitivity of arteries and veins to histamine, and diminished the differences between their maximal responses; the NO synthase inhibitor Nomega-nitro-L-arginine (L-NOARG) increased the maximal responses of arteries and veins, and the differences between their responses; indomethacin had no effect. 4. Contractions to 5-HT were abolished in arteries and markedly reduced in veins by the 5-HT2 antagonist ketanserin (10(-4) M); L-NOARG potentiated the maximal responses of arteries but not of veins; indomethacin increased the maximal responses of arteries but reduced them in veins. 5. By morphometry, arteries had a greater medial thickness and luminal diameter than veins. 6. The data suggest that in guinea-pigs, H2 receptors are responsible for the differential contractile responses of pulmonary arteries and veins to histamine, whereas endothelium-derived vasoactive substances are responsible for their differential contractile responses to 5-HT.
Serotonergic psychedelics, substances exerting their effects primarily through the serotonin 2A receptor (5HT2AR), continue to comprise a substantial portion of reported new psychoactive substances (NPS). In this paper five quantitative structure-activity relationship (QSAR) models for predicting the affinity of 5-HT2AR ligands have been developed. The resulting models, exploiting the accessibility of the QSAR equations, generate a useful tool for the investigation and identification of unclassified molecules. The models have been built using a set of 375 molecules using Forge software, and the quality was confirmed by statistical analysis, resulting in effective tools with respect to their predictive and descriptive capabilities. The best performing algorithm among the machine learning approaches and the classical field 3D-QSAR model were then combined to produce a consensus model and were exploited, together with a pharmacophorefilter, to explore the 5-HT2AR activity of 523 105 natural products, to classify a set of recently reported 5-HT2AR NPS and to design new potential active molecules. The findings of this study should facilitate the identification and classification of emerging 5-HT2AR ligands including NPS.
The plasma concentration of 5-hydroxytryptamine (5-HT) in diabetic patients is higher than that in normal subjects. Since recent reports have demonstrated the presence of 5-HT2A receptor in glomerular mesangial cells, it is possible that 5-HT may be involved in the development of diabetic nephropathy through the 5-HT2A receptor in mesangial cells. Because expansion of the glomerular mesangial lesion is a characteristic feature of diabetic nephropathy, we examined the effect of 5-HT on the production of type IV collagen by human mesangial cells.
Blood pressure reduction is an important and effective strategy in stroke prevention in hypertensives. Recently, we found that baroreflex restoration was also crucial in stroke prevention. The present work was designed to test the hypothesis that a combination of blood pressure reduction and baroreflex restoration may be a new strategy for stroke prevention. In Experiment 1, the effects of ketanserin (0.3, 1, 3, 10 mg/kg), amlodipine (0.3, 1, 2, 3 mg/kg) and their combination (1 + 0.3, 1 + 1, 1 + 2, 1 + 3 mg/kg) on blood pressure and baroreflex sensitivity (BRS) of stroke-prone spontaneously hypertensive rats (SHR-SP) were determined under conscious state. It was found that both amlodipine and ketanserin decreased blood pressure dose-dependently. Ketanserin enfanced BRS from a very small dose but amlodipine enfanced BRS only at largest dose used. At the dose of 1 + 2 mg/kg (ketanserin + amlodipine), the combination possessed the largest synergism on blood pressure reduction. In Experiments 2 and 3, SHR-SP and two-kidney, two-clip (2K2C) renovascular hypertensive rats received life-long treatments with ketanserin (1 mg/kg) and amlodipine (2 mg/kg) or their combination (0.5 + 1, 1 + 2, 2 + 4 mg/kg). The survival time was recorded and the brain lesion was examined. It was found that all kinds of treatments prolonged the survival time of SHR-SP and 2K2C rats. The combination possessed a significantly better effect on stroke prevention than mono-therapies. In conclusion, combination of blood pressure reduction and baroreflex restoration may be a new strategy for the prevention of stroke in hypertension.
Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A-TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A-TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.
Serotonin (5-HT) plays a major yet complex role in modulating spinal nociceptive transmission as a consequence of the number of 5-HT receptor subtypes. These include the 5-HT2 receptor, which is further sub classified into 5-HT2A, B and C. Studies have described both a pro- and antinociceptive action following 5-HT2A-receptor activation; therefore, to shed light on the directional nature of spinal 5-HT2A receptor activity, we investigated the effects of spinal administration of the 5-HT2A receptor antagonist, ketanserin, on the evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimulation. We also assessed the effects of systemic administration of ritanserin, a 5-HT2A/2C receptor antagonist and spinal application of (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) (3.6 and 17.8μg/50μl), a 5-HT2A/2C agonist, on the same evoked neuronal responses. Ketanserin (1, 10 and 100μg/50μl) produced a dose related inhibition of the evoked responses to noxious mechanical punctate and thermal stimuli only. Ritanserin (2mg/kg) replicated the inhibitory effects seen with ketanserin on the natural evoked neuronal responses and also potently inhibited the C-fibre, post discharge, input and wind-up evoked responses. DOI increased the mechanical and thermal evoked responses, an effect reversed by ketanserin. Thus, our findings show that spinal ketanserin (1-100μg/50μl) and systemic ritanserin (2mg/kg), at these doses, have similar antinociceptive effects, whereas the agonist, DOI, produced excitatory effects, on spinal neuronal activity. Our data, therefore, supports a pronociceptive role for 5-HT2 receptors, most likely through modulation of 5-HT2A receptor activity, on spinal nociceptive transmission under normal conditions.
MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT(1) and 5-HT(2) receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT(2) receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT(1) receptors do not appear to be involved in MDMA effects on mood and impulse control.
Ovariectomized rats were hormonally primed with 0.5 microg estradiol benzoate and 500 microg progesterone to produce two groups of rats differing in their lordosis behavior. Females with a lordosis to mount (L/M) ratio < 0.5 were used to test the hypothesis that 5-HT(2A/2C) receptor agonists could facilitate lordosis behavior. Females with L/M ratios > or = 0.5 were used to evaluate the potential suppressive effect of 5-HT(2A/2C) receptor compounds. Lordosis behavior was examined following bilateral infusion of drugs into the ventromedial nucleus of the hypothalamus (VMN). Drugs examined were the 5-HT(2A/2C) receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), the 5-HT(2A/2C) receptor antagonist, 3-[2-[4-(4-fluorobenzoyl)-1-piperdinyl]ethyl]-2,4(1H,3H)-quinazoli nedione tartrate (ketanserin tartrate), and the non-selective 5-HT receptor agents, 2-(1-piperazinyl)quinoline dimaleate (quipazine) and N-(3-trifluoromethylphenyl)piperazine HCl (TFMPP). Drugs with agonist action at 5-HT(2A/2C) receptors increased lordosis behavior in rats with low sexual receptivity. The 5-HT(2A/2C) receptor antagonist, ketanserin, inhibited lordosis behavior in sexually receptive rats. DOI attenuated the lordosis-inhibiting effect of ketanserin, but ketanserin was less effective in preventing DOI from increasing lordosis behavior. These results strengthen prior inferences that activation of 5-HT(2A/2C) receptors can facilitate lordosis behavior and that the VMN is one site at which such facilitation can occur.
1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2. The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50 = 2.9 nM; maximal effect approximately 50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50 = 6.4 nM; maximal effect approximately 50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3. The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity. 4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors. 5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype.
A persistent pulmonary artery hypertension, increased airways resistance, increased vascular permeability to protein, and hypoxia are characteristic of sepsis-induced ARDS in humans and are present in the late phase injury response seen in sheep after endotoxin. Our purpose was to determine the role of serotonin, 5-HT, in the steady-state pulmonary hypertension and decreased arterial oxygen tension seen beginning approximately 3 h after Escherichia coli endotoxin injury (2 micrograms/kg) in the adult sheep. Plasma 5-HT levels remained constant, whereas lung lymph values increased from a baseline of 60 +/- 40 to 180 +/- 70 and 270 +/- 90 ng/ml at 1-h and at 3- to 5-h periods, respectively, after endotoxin. Platelet count decreased significantly only at the 3-h time period. Ketanserin, a 5-HT antagonist, was infused (0.15 mg/kg/h) in 7 sheep during endotoxin injury. The degree of early pulmonary hypertension and hypoxia was not affected by ketanserin. Mean values for pulmonary artery pressure and arterial oxygen tension were 40 +/- 8 mmHg and 70 +/- 8 torr for endotoxin alone and 38 +/- 7 mmHg and 72 +/- 7 torr for the ketanserin group. Steady-state, protein-rich pulmonary perfusion was also not altered, being increased 3-fold in both groups. Pulmonary hypertension and hypoxia were significantly attenuated, however, at the 3- to 5-h period with ketanserin, compared with endotoxin alone, the pulmonary artery pressure decreasing from 29 +/- 5 to 22 +/- 4 mmHg and the PaO2 increasing from 75 +/- 4 to 83 +/- 5 torr.(ABSTRACT TRUNCATED AT 250 WORDS)
Perivascular adipose tissue (PVAT) modulates vascular tone and altered PVAT function is observed in vascular diseases such as hypertension and atherosclerosis. We discovered that the PVAT surrounding rat thoracic aorta (RA) and the superior mesenteric artery (SMA) contain significant amounts of 5-hydroxytryptamine (5-HT). We hypothesized that the 5-HT contained within the PVAT is functional and vasoactive. Isolated tissue baths were used for isometric contractility studies and high performance liquid chromatography was used to quantitatively measure amines in the PVAT and release studies. The 5-HT releaser fenfluramine (10 nM-100 μM) was tested for its ability to contract arteries with and without PVAT. Contraction was reported as a percentage of the initial contraction to 10 μM phenylephrine. The RA with PVAT contracted to fenfluramine to a greater maximum (98 ± 10%) than RA without PVAT (24 ± 4%), while no difference in contraction of SMA to maximum fenfluramine with (78 ± 2%) and without (75 ± 6%) PVAT was observed. Contradicting our hypothesis, the maximum contraction of RA with PVAT to fenfluramine was diminished by the alpha-1 adrenoreceptor antagonist prazosin (100 nM; vehicle: 71 ± 4%, prazosin: 24 ± 2%) and the norepinephrine transporter (NET) inhibitor nisoxetine (1 μM; vehicle: 71 ± 4%, nisoxetine: 25 ± 4%) but not the 5-HT2A/2C receptor antagonist ketanserin (10 nM) or serotonin specific reuptake inhibitor fluoxetine (10 μM). To test if fenfluramine caused release of 5-HT or NE from PVAT, PVAT from RA was incubated with vehicle or fenfluramine (10 μM-10 mM), and amines released into the incubating buffer were quantified. A pronounced concentration-dependent NE-release (more than 5-HT) was observed. Collectively, this research illustrates the pharmacology of fenfluramine to primarily stimulate NE release (better than 5-HT) in a NET-dependent manner, leading to vasoconstriction. This adds additional support to PVAT as being an important reservoir of amines.
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