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1.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063103

RESUMO

This study was aimed at disclosing the influence of intravesically instilled guanethidine (GUA) on the distribution, relative frequency and chemical coding of both the urinary bladder intramural sympathetic nerve fibers and their parent cell bodies in the caudal mesenteric ganglion (CaMG) in juvenile female pigs. GUA instillation led to a profound decrease in the number of perivascular nerve terminals. Furthermore, the chemical profile of the perivascular innervation within the treated bladder also distinctly changed, as most of axons became somatostatin-immunoreactive (SOM-IR), while in the control animals they were found to be neuropeptide Y (NPY)-positive. Intravesical treatment with GUA led not only to a significant decrease in the number of bladder-projecting tyrosine hydroxylase (TH) CaMG somata (94.3 ± 1.8% vs. 73.3 ± 1.4%; control vs. GUA-treated pigs), but simultaneously resulted in the rearrangement of their co-transmitters repertoire, causing a distinct decrease in the number of TH+/NPY+ (89.6 ± 0.7% vs. 27.8 ± 0.9%) cell bodies and an increase in the number of SOM-(3.6 ± 0.4% vs. 68.7 ± 1.9%), calbindin-(CB; 2.06 ± 0.2% vs. 9.1 ± 1.2%) or galanin-containing (GAL; 1.6 ± 0.3% vs. 28.2 ± 1.3%) somata. The present study provides evidence that GUA significantly modifies the sympathetic innervation of the porcine urinary bladder wall, and thus may be considered a potential tool for studying the plasticity of this subdivision of the bladder innervation.


Assuntos
Antagonistas Adrenérgicos/farmacologia , Axônios/fisiologia , Gânglios Simpáticos/fisiologia , Guanetidina/farmacologia , Bexiga Urinária/inervação , Animais , Axônios/efeitos dos fármacos , Dopamina beta-Hidroxilase/metabolismo , Feminino , Gânglios Simpáticos/efeitos dos fármacos , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Neuropeptídeo Y/metabolismo , Suínos , Bexiga Urinária/efeitos dos fármacos
2.
Gastroenterology ; 160(4): 1208-1223.e4, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32980343

RESUMO

BACKGROUND & AIMS: The colon is innervated by intrinsic and extrinsic neurons that coordinate functions necessary for digestive health. Sympathetic input suppresses colon motility by acting on intrinsic myenteric neurons, but the extent of sympathetic-induced changes on large-scale network activity in myenteric circuits has not been determined. Compounding the complexity of sympathetic function, there is evidence that sympathetic transmitters can regulate activity in non-neuronal cells (such as enteric glia and innate immune cells). METHODS: We performed anatomical tracing, immunohistochemistry, optogenetic (GCaMP calcium imaging, channelrhodopsin), and colon motility studies in mice and single-cell RNA sequencing in human colon to investigate how sympathetic postganglionic neurons modulate colon function. RESULTS: Individual neurons in each sympathetic prevertebral ganglion innervated the proximal or distal colon, with processes closely opposed to multiple cell types. Calcium imaging in semi-intact mouse colon preparations revealed changes in spontaneous and evoked neural activity, as well as activation of non-neuronal cells, induced by sympathetic nerve stimulation. The overall pattern of response to sympathetic stimulation was unique to the proximal or distal colon. Region-specific changes in cellular activity correlated with motility patterns produced by electrical and optogenetic stimulation of sympathetic pathways. Pharmacology experiments (mouse) and RNA sequencing (human) indicated that appropriate receptors were expressed on different cell types to account for the responses to sympathetic stimulation. Regional differences in expression of α-1 adrenoceptors in human colon emphasize the translational relevance of our mouse findings. CONCLUSIONS: Sympathetic neurons differentially regulate activity of neurons and non-neuronal cells in proximal and distal colon to promote distinct changes in motility patterns, likely reflecting the distinct roles played by these 2 regions.


Assuntos
Colo/inervação , Gânglios Simpáticos/fisiologia , Motilidade Gastrointestinal/fisiologia , Plexo Mientérico/fisiologia , Animais , Colo/citologia , Colo/efeitos dos fármacos , Colo/fisiologia , Feminino , Gânglios Simpáticos/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Guanetidina/farmacologia , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/inervação , Mucosa Intestinal/fisiologia , Masculino , Camundongos , Modelos Animais , Plexo Mientérico/citologia , Plexo Mientérico/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Optogenética , Prazosina/farmacologia , RNA-Seq , Análise de Célula Única , Ioimbina/farmacologia
3.
Toxicol Pathol ; 48(1): 228-237, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30987556

RESUMO

The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy postganglionic sympathetic neurons in SCG. Following the last dose, animals were allowed to recover 1, 3, or 6 months. Right and left SCG from guanethidine-treated and age-matched, vehicle-treated control rats were harvested for histopathologic, morphometric, and stereologic evaluations. Both morphometric and stereologic evaluations confirmed neuron loss following guanethidine treatment. Morphometric analysis revealed a 50% to 60% lower number of tyrosine hydroxylase (TH)-positive neurons per unit area of SCG at both 3 and 6 months of recovery, compared to ganglia of age-matched controls, with no evidence of restoration of neuron density between 3 and 6 months. Reductions in TH-positive neurons following guanethidine treatment were corroborated by unbiased stereology of total hematoxylin and eosin-stained neuron numbers in SCG. Stereologic analyses revealed that total neuron counts were lower by 37% at 3 months of recovery when compared to age-matched vehicle controls, again with no obvious restoration between 3 and 6 months. Thus, no evidence was found that postganglionic neurons of the sympathetic nervous system in the adult rat have a neurogenic capacity.


Assuntos
Gânglios Simpáticos/fisiologia , Guanetidina/toxicidade , Neurogênese , Simpatolíticos/toxicidade , Animais , Degeneração Neural , Neurônios , Ratos , Sistema Nervoso Simpático , Tirosina 3-Mono-Oxigenase
4.
Hypertens Res ; 42(12): 1872-1882, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31527789

RESUMO

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Hipertensão/fisiopatologia , Simpatolíticos/farmacologia , Vasoconstritores/farmacologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Barorreflexo/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiopatologia , Catecolaminas/metabolismo , Guanetidina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Restrição Física , Estresse Psicológico
5.
Reprod Biol Endocrinol ; 16(1): 86, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30193590

RESUMO

BACKGROUND: The injection of estradiol valerate in female rats induces polycystic ovary syndrome, which is characterized by polycystic ovaries, anovulation, and hyperandrogenism. These characteristics have been associated with an increase in the ovarian concentration of norepinephrine, which occurs before establishing the polycystic ovary syndrome. The bilateral section of the superior ovarian nerve restores ovarian functions in animals with polycystic ovary syndrome. The superior ovarian nerve provides norepinephrine and vasoactive intestinal peptide to the ovary. An increase in the activity of both neurotransmitters has been associated with the development of polycystic ovary syndrome. The purpose of the present study was analyzed the participation of the noradrenergic nervous system in the development of polycystic ovary syndrome using guanethidine as a pharmacological tool that destroys peripheral noradrenergic nerve fibers. METHODS: Fourteen-day old female rats of the CIIZ-V strain were injected with estradiol valerate or vehicle solution. Rats were randomly allotted to one of three guanethidine treatment groups for denervation: 1) guanethidine treatment at age 7 to 27-days, 2) guanethidine treatment at age 14 to 34- days, and 3) guanethidine treatment at age 70 to 90- days. All animals were sacrificed when presenting vaginal oestrus at age 90 to 94-days. The parameters analyzed were the number of ova shed by ovulating animals, the ovulation rate (i.e., the numbers of ovulating animals/the numbers of used animals), the serum concentration of progesterone, testosterone, oestradiol and the immunoreactivity for tyrosine hydroxylase enzyme. All data were analyzed statistically. A p-value of less than 0.05 was considered significant. RESULTS: Our results show that the elimination of noradrenergic fibers before the establishment of polycystic ovary syndrome prevents two characteristics of the syndrome, blocking of ovulation and hyperandrogenism. We also found that in animals that have already developed polycystic ovary syndrome, sympathetic denervation restores ovulatory capacity, but it was not as efficient in reducing hyperandrogenism. CONCLUSION: The results of the present study suggest that the noradrenergic fibers play a stimulant role in the establishment of polycystic ovary syndrome.


Assuntos
Guanetidina/uso terapêutico , Síndrome do Ovário Policístico/patologia , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Estradiol/análogos & derivados , Feminino , Ovário/efeitos dos fármacos , Ovário/inervação , Distribuição Aleatória , Ratos Endogâmicos , Simpatectomia Química , Fatores de Tempo
6.
PLoS One ; 13(9): e0203573, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30199552

RESUMO

Endothelium is the main source of catecholamine release in the electrical-field stimulation (EFS)-induced aortic contractions of the non- venomous snake Panterophis guttatus. However, adrenergic vasomotor control in venomous snakes such as Crotalus durissus terrificus and Bothrops jararaca has not yet been investigated. Crotalus and Bothrops aortic rings were mounted in an organ bath system. EFS-induced aortae contractions were performed in the presence and absence of guanethidine (30 µM), phentolamine (10 µM) or tetrodotoxin (1 µM). Frequency-induced contractions were also performed in aortae with endothelium removed. Immunohistochemical localization of both tyrosine hydroxylase (TH) and S-100 protein in snake aortic rings and brains, as well as in human tissue (paraganglioma tumour) were carried out. EFS (4 to 16 Hz) induced frequency-dependent aortic contractions in both Crotalus and Bothrops. The EFS-induced contractions were significantly reduced in the presence of either guanethidine or phentolamine in both snakes (p<0.05), whereas tetrodotoxin had no effect in either. Removal of the endothelium abolished the EFS-induced contractions in both snakes aortae (p<0.05). Immunohistochemistry revealed TH localization in endothelium of both snake aortae and human vessels. Nerve fibers were not observed in either snake aortae. In contrast, both TH and S100 protein were observed in snake brains and human tissue. Vascular endothelium is the main source of catecholamine release in EFS-induced contractions in Crotalus and Bothrops aortae. Human endothelial cells also expressed TH, indicating that endothelium- derived catecholamines possibly occur in mammalian vessels.


Assuntos
Aorta/efeitos dos fármacos , Bothrops/metabolismo , Catecolaminas/metabolismo , Crotalus/metabolismo , Estimulação Elétrica , Animais , Catecolaminas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Guanetidina/metabolismo , Guanetidina/farmacologia , Técnicas In Vitro , Fentolamina/metabolismo , Fentolamina/farmacologia , Proteínas S100/metabolismo , Tetrodotoxina/metabolismo , Tetrodotoxina/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo
7.
PLoS One ; 13(8): e0202182, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30106981

RESUMO

Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver in response to metabolic stress. In addition to its well-characterized effects on energy homeostasis, FGF21 has been shown to increase water intake in animals. In this study, we sought to further explore the effects of FGF21 on fluid homeostasis in rats. A single dose of a long-acting FGF21 analog, PF-05231023, significantly increased water consumption, which was accompanied by an elevation in urine output that appeared prior to a significant change in water intake. We observed that FGF21 rapidly and significantly increased heart rate and blood pressure in telemeter-implanted rats, before changes in urine output and water intake were observed. Our data suggest that sympathetic activation may contribute to the pathogenesis by which FGF21 increases blood pressure as the baroreceptor unloading induced reflex tachycardia was significantly elevated in FGF21-treated animals. However, FGF21 was still capable of causing hypertension in animals in which approximately 40% of the sympathetic post-ganglionic neurons were ablated. Our data suggest that FGF21-induced water intake is in fact secondary to diuresis, which we propose to be a compensatory mechanism engaged to alleviate the acute hypertension caused by FGF21.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Diurese/efeitos dos fármacos , Diuréticos/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Preparações de Ação Retardada , Diurese/fisiologia , Ingestão de Líquidos/fisiologia , Água Potável , Eletrólitos/sangue , Eletrólitos/urina , Fatores de Crescimento de Fibroblastos/metabolismo , Guanetidina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Ratos Wistar
8.
Georgian Med News ; (274): 149-152, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29461244

RESUMO

It is known that in some pathological conditions, due to the formation of a large number of free oxygen radicals, the cardiovascular system is severely affected. However, the effect of free radicals on CGRP-mediated vasodilation remains unclear. The aim of this work was to study the effect of free radicals on CGRP-mediated neurogenic vasodilation on preparations of an isolated rabbit lingual artery. The experiments were performed on the lingual artery preparations of 6 rabbits of the Chinchilla breed of both sexes. The contractile-relaxation activity of isolated preparations, both with intact endothelial layer and deendotelized, were studied in isometric mode on a strain-gauge unit using mechanotrons of the 6 MX1C type. Our experiments showed that free radicals can disrupt the reactivity of the vascular wall both in the presence and in the absence of endothelium-dependent relaxation factors and that is might be considered as a main conclusion of this study.


Assuntos
Artérias/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Radical Hidroxila/farmacologia , Contração Isométrica/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Acetilcolina/farmacologia , Animais , Artérias/citologia , Artérias/fisiologia , Estimulação Elétrica , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Guanetidina/farmacologia , Masculino , Soalho Bucal/irrigação sanguínea , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Norepinefrina/farmacologia , Coelhos , Técnicas de Cultura de Tecidos
9.
Reproduction ; 155(2): 173-181, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29162649

RESUMO

Recently, the influence of adrenergic activity over ovarian function, and thus fertility, has begun to gain importance. Previous studies have shown that adrenergic activity through norepinephrine (NE) participates in the control of follicular development and steroidal secretion from the ovary, among other functions. To examine this phenomenon, the denervation of the gonad has been widely used to observe changes in the ovary's performance. Nevertheless, the effect of the absence of adrenergic nerves in the ovary has only been studied in short times periods. In the present work, we used guanethidine (a drug that produces an irreversible sympathectomy) during the infantile period of rats, and we observed its effects in the adult rat (6 months old). Our results indicate that ovarian NE content is recovered at 6 months old, alongside with an increase of the adrenal content of NE and a dysfunctional celiac ganglion. Together, these results suggest that the recovery of ovarian NE does not come from a neural origin. In addition, ovarian performance was impaired because the changes in follicular development and steroidal secretion are not recovered despite the recovery of ovarian NE content. In conclusion, these results suggest that the nerve-ovarian connections, which are established during infantile development, are necessary for the accurate response of the ovary to sympathetic stimulation.


Assuntos
Estradiol/metabolismo , Norepinefrina/metabolismo , Folículo Ovariano/citologia , Simpatectomia , Sistema Nervoso Simpático/cirurgia , Animais , Feminino , Guanetidina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/cirurgia , Ratos , Ratos Sprague-Dawley , Simpatolíticos/farmacologia
10.
J Pharm Pharmacol ; 69(12): 1754-1761, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28836276

RESUMO

OBJECTIVES: Alpha7 nicotinic acetylcholine receptor (α7-nAChR), an emerging pharmacological target for a variety of medical conditions, is expressed in the most mammalian tissues with different effects. So, this study was designed to investigate the expression, localization and effect of α7-nAChR in rat corpus cavernosum (CC). METHODS & KEY FINDINGS: Reverse transcription polymerase chain reaction (RT-PCR) revealed that α7-nAChR was expressed in rat CC and double immunofluorescence studies demonstrated the presence of α7-nAChR in corporal neurons. The rat CC segments were mounted in organ bath chambers and contracted with phenylephrine (0.1 µm -300 µm) to investigate the relaxation effect of electrical field stimulation (EFS,10 Hz) assessed in the presence of guanethidine (adrenergic blocker, 5 µm) and atropine (muscarinic cholinergic blocker, 1 µm) to obtain non-adrenergic non-cholinergic (NANC) response. Cumulative administration of nicotine significantly potentiated the EFS-induced NANC relaxation (-log EC50 = 7.5 ± 0.057). Whereas, the potentiated NANC relaxation of nicotine was significantly inhibited with different concentrations of methyllycaconitine citrate (α7-nAChR antagonist, P < 0.05) in preincubated strips. L-NAME (non-specific nitric oxide synthase inhibitor, 1 µm) completely blocked the neurogenic relaxation induced by EFS plus nicotine. CONCLUSION: To conclude α7-nAChR is expressed in rat CC and modulates the neurogenic relaxation response to nicotine.


Assuntos
Nicotina/administração & dosagem , Pênis/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Aconitina/administração & dosagem , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Atropina/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Guanetidina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nicotina/farmacologia , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
Auton Neurosci ; 206: 19-27, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28688831

RESUMO

Existing experimental studies of the effect of sympathetic nerve fibers on bone marrow cells are based on the systemic administration of neurotoxic 6-hydroxydopamine. The method of global chemical sympathectomy has some serious disadvantages and could lead to questionable results. We describe a new method of local chemical sympathectomy of rat femoral bone marrow using guanethidine (Ismelin) delivery using an osmotic mini pump. Local guanethidine treatment for 14days led to complete elimination of sympathetic fibers in femoral bone marrow in contrast to bone marrow of contralateral or naïve femurs. Ablation of sympathetic fibers was associated with a loss of rat endothelial cell marker (RECA) indicating immunophenotype changes in blood vessel endothelial cells, but no significant effect of guanethidine was found on the survival of endothelial cells and mesenchymal stem cells in vitro. Moreover, local guanethidine treatment also elicited a significant reduction of Nestin+/SDF1+ mesenchymal stem cells and c-Kit+/CD90+ hematopoietic stem cells in femoral bone marrow. Tissue-specific chemical sympathectomy of rat bone marrow by guanethidine overcomes some of the drawbacks of systemic administration of neurotoxic compounds like 6-hydroxydopamine and delivers unequivocal evidence on the effects of sympathetic innervation on the cell content of bone marrow.


Assuntos
Medula Óssea/inervação , Guanetidina/farmacologia , Simpatolíticos/farmacologia , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Fêmur/efeitos dos fármacos , Fêmur/inervação , Fêmur/metabolismo , Fêmur/patologia , Citometria de Fluxo , Imunofluorescência , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Modelos Animais , Ratos Wistar , Simpatectomia Química , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/patologia
12.
J Pharmacol Toxicol Methods ; 88(Pt 1): 64-71, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28658603

RESUMO

The purpose of this study was to evaluate functional measures of diminished sympathetic activity after postganglionic neuronal loss in the conscious rat. To produce variable degrees of sympathetic postganglionic neuronal loss, adult rats were treated daily with toxic doses of guanethidine (100mg/kg) for either 5days or 11days, followed by a recovery period of at least 18days. Heart rate, blood pressure, cardiac baroreflex responsiveness, urinalysis (for catecholamine metabolite, 3-methoxy-4-hydroxyphenylethylenglycol; MHPG), and pupillometry were performed during the recovery period. At the end of the recovery period stereology of superior cervical ganglia (SCG) was performed to determine the degree of neuronal loss. Total number of SCG neurons was correlated to physiological outcomes using regression analysis. Whereas guanethidine treatment for 11days caused significant reduction in the number of neurons (15,646±1460 vs. 31,958±1588), guanethidine treatment for 5days caused variable levels of neuronal depletion (26,009±3518). Regression analysis showed that only changes in urinary MHPG levels and systolic blood pressure significantly correlated with reduction of SCG neurons (r2=0.45 and 0.19, both p<0.05). Although cardiac baroreflex-induced reflex tachycardia (345.7±19.6 vs. 449.7±20.3) and pupil/iris ratio (0.50±0.03% vs. 0.61±0.02%) were significantly attenuated in the 11-day guanethidine treated rats there was no significant relationship between these measurements and the number of remaining SCG neurons after treatment (p>0.05). These data suggest that basal systolic blood pressure and urinary MHPG levels predict drug-induced depletion of sympathetic activity in vivo.


Assuntos
Guanetidina/toxicidade , Neurônios/efeitos dos fármacos , Gânglio Cervical Superior/efeitos dos fármacos , Simpatolíticos/toxicidade , Testes de Toxicidade Aguda/métodos , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/metabolismo , Estado de Consciência , Frequência Cardíaca/efeitos dos fármacos , Masculino , Metoxi-Hidroxifenilglicol/urina , Ratos , Ratos Sprague-Dawley
13.
Artigo em Inglês | MEDLINE | ID: mdl-28332745

RESUMO

BACKGROUND: In the gastrointestinal tract of several species, facilitating 5-HT4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5-HT4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract. METHODS: In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride. KEY RESULTS: Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 µmol/L onwards. The facilitation in the different series with 0.03 µmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 µmol/L prucalopride was concentration-dependently inhibited by GR 113808. CONCLUSIONS & INFERENCES: In the murine gastrointestinal tract, activation of 5-HT4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species.


Assuntos
Acetilcolina/fisiologia , Trato Gastrointestinal/fisiologia , Receptores 5-HT4 de Serotonina/fisiologia , Transmissão Sináptica , Animais , Benzofuranos/administração & dosagem , Colo/efeitos dos fármacos , Colo/fisiologia , Nucleotídeos de Desoxiadenina/administração & dosagem , Estimulação Elétrica , Fundo Gástrico/efeitos dos fármacos , Fundo Gástrico/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Guanetidina/administração & dosagem , Hexametônio/administração & dosagem , Jejuno/efeitos dos fármacos , Jejuno/fisiologia , Masculino , Mecamilamina/administração & dosagem , Camundongos Endogâmicos C57BL , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , NG-Nitroarginina Metil Éster/administração & dosagem , Agonistas do Receptor 5-HT4 de Serotonina/administração & dosagem
14.
EuroIntervention ; 12(18): e2262-e2270, 2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27890860

RESUMO

AIMS: The aim of the study was to evaluate the feasibility, safety and efficacy of renal sympathetic denervation with CT-guided periarterial injection of potentially neurolytic agents in pigs. METHODS AND RESULTS: Unilateral injection of formulations containing either 5M hyperosmolar saline, vincristine, paclitaxel or guanethidine around the renal artery was performed in 24 normotensive pigs with six animals per group. Needle placement and injections were performed under CT fluoroscopy guidance. Blood pressure measurements and CT scans were performed immediately before and after the intervention and four weeks after treatment. After euthanasia, norepinephrine (NE) concentrations of both kidneys were determined. The renal arteries and surrounding tissue were examined histologically to evaluate nerve fibre degeneration. Procedures were technically successful with good periarterial distribution of the injectant in all but one pig in the guanethidine group. No major adverse events or post-interventional complications occurred. In the vincristine group, NE concentrations of the renal parenchyma were lower on the treated side in all pigs with a mean decrease of 53% (38%-62%, p<0.01) compared to the contralateral control. Correspondingly, histological examination revealed neural degeneration in all animals treated with vincristine. In the other groups, no significant drop of NE values, or histological signs of nerve fibre degeneration were found. CONCLUSIONS: CT-guided periarterial injection of the different substances was feasible and safe. Renal sympathetic denervation was achieved with vincristine. In contrast, hyperosmolar saline, paclitaxel and guanethidine do not seem to be appropriate for renal denervation in a pig model at the dosage used.


Assuntos
Guanetidina/administração & dosagem , Rim/inervação , Paclitaxel/administração & dosagem , Simpatectomia/métodos , Tomografia Computadorizada por Raios X/métodos , Vincristina/administração & dosagem , Animais , Pressão Sanguínea , Rim/química , Rim/diagnóstico por imagem , Rim/patologia , Norepinefrina/análise , Suínos
15.
Artigo em Inglês | MEDLINE | ID: mdl-27085835

RESUMO

The goal of this study was to determine the degree of sympathetic postganglionic neuronal loss required to impair cardiovascular-related sympathetic activity. To produce neuronal loss separate groups of rats were treated daily with guanethidine for either 5days or 11days, followed by a recovery period. Sympathetic activity was measured by renal sympathetic nerve activity (RSNA). Stereology of thoracic (T13) ganglia was performed to determine neuronal loss. Despite loss of more than two thirds of neurons in T13 ganglia in both treated groups no effect on resting blood pressure (BP) or heart rate (HR) was detected. Basal RSNA in rats treated for 5days (0.61±0.10µV∗s) and 11days (0.37±0.08µV∗s) was significantly less than vehicle-treated rats (0.99±0.13µV∗s, p<0.05). Increases in RSNA by baroreceptor unloading were significantly lower in 5-day (1.09±0.19µV∗s) and 11-day treated rats (0.59±0.11µV∗s) compared with vehicle-treated rats (1.82±0.19µV∗s, p<0.05). Increases in RSNA to chemoreceptor stimulation were significantly lower in 5-day treated rats (1.54±0.25µV∗s) compared with vehicle-treated rats (2.69±0.23µV∗s, p<0.05). Increases in RSNA in 11-day treated rats were significantly lower (0.75±0.15µV∗s, p<0.05) compared with both vehicle-treated and 5-day treated rats. A positive correlation of neurons to sympathetic responsiveness but not basal activity was detected. These data suggest that diminished capacity for reflex sympathetic responsiveness rather than basal activity alone must be assessed for complete detection of neurophysiological cardiovascular impairment.


Assuntos
Anestesia/efeitos adversos , Sistema Cardiovascular/efeitos dos fármacos , Fibras Simpáticas Pós-Ganglionares , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sistema Cardiovascular/inervação , Guanetidina/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/inervação , Masculino , Pressorreceptores/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Simpatolíticos/toxicidade , Nervos Torácicos
16.
Planta Med ; 82(15): 1329-1334, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27124242

RESUMO

α-Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, α-terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by α-terpineol, but atropine and L-NG-nitroarginine methyl ester abolished it. In vagotomized rats, α-terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration-effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. α-Terpineol (1 to 2000 µM) relaxed sustained contractions induced by carbamylcholine or a high K+ concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-NG-nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by α-terpineol. In conclusion, α-terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by α-terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells.


Assuntos
Cicloexenos/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Fundo Gástrico/efeitos dos fármacos , Monoterpenos/farmacologia , Nervo Vago/efeitos dos fármacos , Animais , Atropina/farmacologia , Carbacol/farmacologia , Monoterpenos Cicloexânicos , Cicloexenos/administração & dosagem , Relação Dose-Resposta a Droga , Esvaziamento Gástrico/fisiologia , Guanetidina/farmacologia , Masculino , Monoterpenos/administração & dosagem , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Técnicas de Cultura de Órgãos , Potássio/farmacologia , Ratos Wistar , Simpatolíticos/farmacologia , Vagotomia , Nervo Vago/metabolismo , Nervo Vago/cirurgia
17.
Biol Psychiatry ; 79(10): 803-813, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26281717

RESUMO

BACKGROUND: Neuroinflammatory signaling may contribute to the pathophysiology of chronic anxiety disorders. Previous work showed that repeated social defeat (RSD) in mice promoted stress-sensitization that was characterized by the recurrence of anxiety following subthreshold stress 24 days after RSD. Furthermore, splenectomy following RSD prevented the recurrence of anxiety in stress-sensitized mice. We hypothesize that the spleen of RSD-exposed mice became a reservoir of primed monocytes that were released following neuroendocrine activation by subthreshold stress. METHODS: Mice were subjected to subthreshold stress (i.e., single cycle of social defeat) 24 days after RSD, and immune and behavioral measures were taken. RESULTS: Subthreshold stress 24 days after RSD re-established anxiety-like behavior that was associated with egress of Ly6C(hi) monocytes from the spleen. Moreover, splenectomy before RSD blocked monocyte trafficking to the brain and prevented anxiety-like behavior following subthreshold stress. Splenectomy, however, had no effect on monocyte accumulation or anxiety when determined 14 hours after RSD. In addition, splenocytes cultured 24 days after RSD exhibited a primed inflammatory phenotype. Peripheral sympathetic inhibition before subthreshold stress blocked monocyte trafficking from the spleen to the brain and prevented the re-establishment of anxiety in RSD-sensitized mice. Last, ß-adrenergic antagonism also prevented splenic monocyte egress after acute stress. CONCLUSIONS: The spleen served as a unique reservoir of primed monocytes that were readily released following sympathetic activation by subthreshold stress that promoted the re-establishment of anxiety. Collectively, the long-term storage of primed monocytes in the spleen may have a profound influence on recurring anxiety disorders.


Assuntos
Ansiedade/fisiopatologia , Monócitos/fisiologia , Baço/fisiopatologia , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Ansiedade/etiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Estudos de Coortes , Modelos Animais de Doenças , Dominação-Subordinação , Guanetidina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Baço/efeitos dos fármacos , Esplenectomia , Estresse Psicológico/complicações , Sistema Nervoso Simpático/efeitos dos fármacos , Simpatolíticos/farmacologia
18.
Auton Neurosci ; 194: 8-16, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26657181

RESUMO

Prostatic smooth muscle develops spontaneous myogenic tone which is modulated by autonomic neuromuscular transmission. This study aimed to investigate the role of purinergic transmission in regulating electrical activity of prostate smooth muscle and whether its contribution may be altered with age. Intracellular recordings were simultaneously made with isometric tension recordings in smooth muscle preparations of the guinea-pig prostate. Immunostaining for P2X1 receptors on whole mount preparations was also performed. In prostate preparations which generated spontaneous slow waves, electrical field stimulation (EFS)-evoked excitatory junction potentials (EJPs) which were abolished by guanethidine (10 µM), α-ß-methylene ATP (10 µM) or pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (PPADS, 10 µM) but not phentolamine (1 µM). Consistently, immunostaining revealed the expression of P2X1 receptors on prostatic smooth muscle. EJPs themselves did not cause contractions, but EJPs could sum to trigger a slow wave and associated contraction. Yohimbine (1 µM) and 3,7-dimethyl-1-propargylxanthine (DMPX, 10 µM) but not propranolol (1 µM) potentiated EJPs. Although properties of EJPs were not different between young and aging guinea-pig prostates, ectoATPase inhibitor ARL 67156 (100 µM) augmented EJP amplitudes by 64.2 ± 29.6% in aging animals, compared to 22.1 ± 19.9% in young animals. These results suggest that ATP released from sympathetic nerves acts on P2X1 purinoceptors located on prostate smooth muscle to evoke EJPs, while pre-junctional α2-adrenergic and adenosine A2 receptors may play a role in preventing excessive transmitter release. Age-related up-regulation of enzymatic ATP breakdown may be a compensatory mechanism for the enhanced purinergic transmission which would cause hypercontractility arising from increased ATP release in older animals.


Assuntos
Estimulação Elétrica , Potenciais da Membrana/fisiologia , Músculo Liso/fisiologia , Próstata , Receptores Purinérgicos P2X1/metabolismo , Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Fatores Etários , Anestésicos Locais/farmacologia , Animais , Guanetidina/farmacologia , Cobaias , Masculino , Potenciais da Membrana/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Purinérgicos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tetrodotoxina/farmacologia , Ioimbina/farmacologia
19.
Mol Pain ; 11: 59, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26376854

RESUMO

BACKGROUND: Cuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16 weeks in male rats, changes in sensory and autonomic innervation of the skin were described after cuff and SNI using immunohistochemistry to label myelinated (neurofilament 200 positive-NF200+) and peptidergic (calcitonin gene-related peptide positive-CGRP+) primary afferents and sympathetic fibres (dopamine ß-hydroxylase positive-DBH+) RESULTS: Cuff and SNI caused an early loss and later reinnervation of NF200 and CGRP fibres in the plantar hind paw skin. In both models, DBH+ fibres sprouted into the upper dermis of the plantar skin 4 and 6 weeks after injury. Despite these similarities, behavioural pain measures were significantly different in each model. Sympathectomy using guanethidine significantly alleviated mechanical allodynia 6 weeks after cuff, when peak sympathetic sprouting was observed, having no effect at 2 weeks, when fibres were absent. In SNI animals, mechanical allodynia in the lateral paw was significantly improved by guanethidine at 2 and 6 weeks, and the development of cold hyperalgesia, which roughly paralleled the appearance of ectopic sympathetic fibres, was alleviated by guanethidine at 6 weeks. Sympathetic fibres did not sprout into the dorsal root ganglia at 2 or 6 weeks, indicating their unimportance to pain behaviour in these two models. CONCLUSIONS: Alterations in sympathetic innervation in the skin represents an important mechanism that contributes to pain in cuff and SNI models of neuropathic pain.


Assuntos
Fibras Adrenérgicas/metabolismo , Neuralgia/patologia , Nervo Isquiático/patologia , Pele/inervação , Fibras Adrenérgicas/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Temperatura Baixa , Derme/efeitos dos fármacos , Derme/inervação , Derme/patologia , Modelos Animais de Doenças , Dopamina beta-Hidroxilase/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Guanetidina/farmacologia , Hiperalgesia/complicações , Hiperalgesia/patologia , Masculino , Neuralgia/complicações , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Simpatectomia
20.
Life Sci ; 130: 7-11, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25818186

RESUMO

AIMS: We evaluated the role of adrenergic systems on the peripheral antinociception induced by dipyrone and diclofenac. Mainmethods: The rat pawpressure test, inwhich sensitivity is increased by intraplantar injection of prostaglandin E2, was used to examine the peripheral effects of locally administered drugs. KEY FINDINGS: Dipyrone (10, 20 and 40 µg) and diclofenac (5, 10 and 20 µg) administered locally into the right paw elicited a dose-dependent antinociceptive effect, which was demonstrated to be local; the injection of drugs into the ipsilateral and contralateral hindpaws demonstrated an effect only in the ipsilateral paw because only the treated paw produced an antinociceptive effect. To test the adrenergic system, we used guanethidine (30 mg/kg) to deplete noradrenalin from noradrenergic vesicles. Guanethidine antagonized the peripheral antinociception induced by diclofenac and dipyrone. Yohimbine (2.5, 5, 10, or 20 µg/paw) a nonselective α2-adrenergic receptor antagonist antagonized the peripheral antinociception induced by diclofenac (20 µg/paw) and dipyrone (40 µg/paw). Rauwolscine (Rau; 10, 15, 20 µg), a selective α2C-adrenoreceptor, was able to block the peripheral antinociception induced by NSAIDs. The other specific α2A,B and D-adrenoreceptor antagonists (BRL 44480, imiloxan and RX 821002, respectively) did not modify the peripheral antinociception. However, prazosin (0.5, 1, and 2 µg/paw), an α1 receptor antagonist, and propranolol (0.3, 0.6 or 1.2 µg/paw), a ß-adrenoreceptor antagonist, antagonized the antinociception induced by diclofenac (20 µg/paw) and dipyrone (40 µg/paw). SIGNIFICANCE: Dipyrone and diclofenac produce peripheral antinociception, which involves the release of NA and interaction with α1, α2C and ß-adrenoreceptors.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Dipirona/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Dipirona/administração & dosagem , Relação Dose-Resposta a Droga , Guanetidina/farmacologia , Masculino , Norepinefrina/metabolismo , Prazosina/administração & dosagem , Prazosina/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Ioimbina/administração & dosagem , Ioimbina/farmacologia
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