RESUMO
BACKGROUND: The role of the neurogenic pathway in early phases of cardioprotection during remote ischemic preconditioning (RIPC) and adenosine preconditioning is reported. AIM: This study was designed to explore the involvement of the neurogenic pathway in late phases of cardioprotection during RIPC and adenosine preconditioning. MATERIAL AND METHODS: Fifty-four Wistar rats were used and divided into 9 experimental groups. RIPC was induced by tying the blood pressure cuff around the hind limb and subjecting to 4 cycles of inflation and deflation of 5 minutes each. In early RIPC, the heart was isolated immediately after the last episode of RIPC, whereas in late RIPC, the heart was isolated 24 hours after the last cycle of RIPC. In a similar way, adenosine preconditioning was instituted in early and late phases by either isolating the heart 40 minutes or 24 hours after adenosine (4 mg/kg, intraperitoneally [i.p.]) administration. Isolated hearts were subjected to ischemia-reperfusion (I/R) injury on the Langendorff's system. RESULTS: Both early and late phases of RIPC and adenosine preconditioning significantly abrogated I/R-induced myocardial injury in terms of decrease in the release of lactate dehydrogenase, creatine kinase, and decrease in infarct size. Pretreatment with hexamethonium, a ganglion blocker (20 mg/kg, i.p.), significantly abolished the cardioprotective effects of both early and late phases of RIPC and adenosine preconditioning. CONCLUSION: Apart from the involvement of the neurogenic pathway in the early phases, there is a critical role of the neurogenic pathway in the late phase of cardioprotection during RIPC and adenosine preconditioning.
Assuntos
Adenosina/administração & dosagem , Sistema Nervoso Autônomo/efeitos dos fármacos , Coração/efeitos dos fármacos , Membro Posterior/irrigação sanguínea , Precondicionamento Isquêmico/métodos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Oclusão Terapêutica , Animais , Sistema Nervoso Autônomo/fisiopatologia , Creatina Quinase/sangue , Modelos Animais de Doenças , Bloqueadores Ganglionares/farmacologia , Coração/inervação , Hexametônio/farmacologia , Preparação de Coração Isolado , L-Lactato Desidrogenase/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos Wistar , Fluxo Sanguíneo Regional , Fatores de TempoRESUMO
NEW FINDINGS: What is the central question of this study? Chronic intermittent hypoxia (CIH) and one-kidney, one-clip experimental models lead to sympathetic overactivity and hypertension. The present study explored the impact of previous exposure to CIH on one-kidney, one-clip renal hypertension; we hypothesized that CIH potentiates its development. What is the main finding and its importance? The development of one-kidney, one-clip renal hypertension was attenuated by previous exposure to CIH, and this protective effect was eliminated by carotid body denervation. These findings indicate that inputs from peripheral chemoreceptors in CIH-preconditioned rats play a role in preventing the increase in sympathetic activity and arterial pressure induced by one-kidney, one-clip renal hypertension. ABSTRACT: Chronic intermittent hypoxia (CIH) and one-kidney, one-clip (1K, 1C) experimental models lead to sympathetic overactivity and hypertension. We hypothesized that previous exposure to CIH potentiates the development of 1K, 1C renal hypertension. Male rats were divided into the following four groups: Control-1K, 1C, maintained under normoxia followed by 1K, 1C surgery (n = 19); Control-Sham, maintained under normoxia, followed by sham surgery (n = 19); CIH-1K, 1C, exposed to CIH (10 days) and 1K, 1C surgery (n = 19); and CIH-Sham, exposed to CIH and sham surgery (n = 18). Animals were catheterized 8 days after 1K, 1C or Sham surgeries and cardiovascular and respiratory parameters recorded on the following day. Baseline mean arterial pressure was higher in Control-1K, 1C than in Control-Sham rats (P < 0.05) and was higher in CIH-1K, 1C than in CIH-Sham rats (P < 0.05). However, the increase in mean arterial pressure in CIH-1K, 1C animals was significantly blunted in comparison to Con-1K, 1C rats (P < 0.05), indicating that previous exposure to CIH attenuates the development of renal hypertension. Systemic administration of hexamethonium, a ganglionic blocker, promoted a larger hypotensive response in Con-1K, 1C compared with CIH-1K, 1C rats (P < 0.05), suggesting that sympathetic activity was attenuated in rats previously exposed to the CIH protocol. In addition, removal of the carotid bodies before 1K, 1C renal hypertension eliminated the protective effect of CIH preconditioning on the development of the 1K, 1C hypertension. We conclude that previous exposure to CIH attenuates the development of renal hypertension via a carotid body-dependent mechanism.
Assuntos
Hipertensão Renal/fisiopatologia , Hipóxia/fisiopatologia , Rim/fisiopatologia , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/fisiopatologia , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Hipertensão Renal/induzido quimicamente , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologiaRESUMO
We examined bladder and urethral sphincter activity in mice with or without spinal cord injury (SCI) after C-fiber afferent desensitization induced by capsaicin pretreatment and changes in electrophysiological properties of mouse bladder afferent neurons 4 wk after SCI. Female C57BL/6N mice were divided into four groups: 1) spinal intact (SI)-control, 2) SI-capsaicin pretreatment (Cap), 3) SCI-control, and 4) SCI-Cap groups. Continuous cystometry and external urethral sphincter (EUS)-electromyogram (EMG) were conducted under an awake condition. In the Cap groups, capsaicin (25, 50, or 100 mg/kg) was injected subcutaneously 4 days before the experiments. In the SI-Cap group, 100 mg/kg capsaicin pretreatment significantly increased bladder capacity and decreased the silent period duration of EUS/EMG compared with the SI-control group. In the SCI-Cap group, 50 and 100 mg/kg capsaicin pretreatment decreased the number of nonvoiding contractions (NVCs) and the duration of reduced EUS activity during voiding, respectively, compared with the SCI-control group. In SCI mice, hexamethonium, a ganglionic blocker, almost completely blocked NVCs, suggesting that they are of neurogenic origin. Patch-clamp recordings in capsaicin-sensitive bladder afferent neurons from SCI mice showed hyperexcitability, which was evidenced by decreased spike thresholds and increased firing rate compared with SI mice. These results indicate that capsaicin-sensitive C-fiber afferent pathways, which become hyperexcitable after SCI, can modulate bladder and urethral sphincter activity in awake SI and SCI mice. Detrusor overactivity as shown by NVCs in SCI mice is significantly but partially dependent on capsaicin-sensitive C-fiber afferents, whereas the EUS relaxation during voiding is enhanced by capsaicin-sensitive C-fiber bladder afferents in SI and SCI mice.
Assuntos
Capsaicina/farmacologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Fármacos do Sistema Sensorial/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Uretra/inervação , Bexiga Urinária Hiperativa/prevenção & controle , Bexiga Urinária/inervação , Micção/efeitos dos fármacos , Potenciais de Ação , Animais , Modelos Animais de Doenças , Eletromiografia , Feminino , Bloqueadores Ganglionares/farmacologia , Camundongos Endogâmicos C57BL , Fibras Nervosas Amielínicas/metabolismo , Neurônios Aferentes/metabolismo , Técnicas de Patch-Clamp , Pressão , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Fatores de Tempo , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/fisiopatologia , Urodinâmica/efeitos dos fármacosRESUMO
Perinatal growth restriction (GR) is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal GR programmes hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy (OVX) oestrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the tenth percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-OVX and post-OVX with oral oestrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122 ± 2; GR 119 ± 2; control-OVX 116 ± 3; GR-OVX 126 ± 3 mmHg). Oestrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23 ± 7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by oestrogen (40 ± 25% increase in high frequency spectral power, P<0.05). In conclusion, GR alters cardiac morphology and cardiovascular regulation. The haemodynamic consequences of GR are attenuated in ovarian-sufficient or oestrogen-replete females. Further investigations are needed to define the role of hormone replacement therapy targeted towards young women with oestrogen deficiency and additional cardiovascular risk factors, including perinatal GR, cardiac hypertrophy and morning surge hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Sistema Cardiovascular/efeitos dos fármacos , Ritmo Circadiano , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios , Hipertensão/prevenção & controle , Ovariectomia , Adaptação Fisiológica , Administração Oral , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/inervação , Modelos Animais de Doenças , Feminino , Bloqueadores Ganglionares/farmacologia , Frequência Cardíaca , Hipertensão/etiologia , Hipertensão/fisiopatologia , Camundongos Endogâmicos C57BL , Atividade Motora , Antagonistas Nicotínicos/farmacologia , Fatores de TempoRESUMO
AIMS: Dental pulp is the specialized tissue responsible for maintaining tooth viability. When tooth mineralized matrix is damaged, pulp is exposed to a plethora of environmental stimuli. In particular, in smokers, pulp become exposed to very high concentrations of nicotine. The aim of this study was to investigate the effect of direct nicotine stimulation on human dental pulp cell proliferation. Moreover, as it is known that nicotine could upregulate the expression of matrix metalloproteinases (MMPs), enzymes involved in pulpal inflammation, the effects of nicotine stimulation on MMP-2 and MMP-28 gene expression have also been investigated. MAIN METHODS: Human dental pulp cells were extracted from impacted third molars obtained from healthy patients undergoing routine orthodontic treatments. Such cells were treated with growing concentrations of nicotine in the presence or absence of a nicotine antagonist (hexamethonium chloride) or of a MEK signaling inhibitor (PD98059). Cell proliferation was evaluated by cell counting, while nicotine effects on MMP expression were evaluated by PCR. KEY FINDINGS: The data obtained indicate that nicotine is able to increase human dental pulp cell proliferation by acting through nicotinic cholinergic receptors and downstream MAPK signaling pathway. Moreover, it is also able to increase both MMP-2 and MMP-28 gene expression. SIGNIFICANCE: In summary these results highlight that direct exposure of human dental pulp cells to nicotine results in an inflammatory response, that could have a role in pulpal inflammation onset, a pathological condition that, when ignored, could eventually spread to the surrounding alveolar bone and progress to pulp necrosis.
Assuntos
Polpa Dentária/enzimologia , Estimulantes Ganglionares/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinases da Matriz Secretadas/biossíntese , Nicotina/farmacologia , Regulação para Cima/efeitos dos fármacos , Adolescente , Adulto , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Polpa Dentária/citologia , Feminino , Flavonoides/farmacologia , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Humanos , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Nicotina/antagonistas & inibidoresRESUMO
BACKGROUND: The aim of the present study was to investigate the effects of the intracolonic transient receptor potential (TRP) A1 agonist allyl isothiocyanate (AITC) on colonic motility and defecation. METHODS: The effects of AITC administered into the proximal colonic lumen on colonic motility and defecation were studied in neurally intact dogs equipped with strain-gauge force transducers on the colon, with or without various antagonists. Effects of intracolonic AITC were also studied in dogs with either transection/re-anastomosis (T/R) between the proximal and middle colon and complete extrinsic denervation of an ileocolonic segment. RESULTS: AITC increased colonic motility and induced giant migrating contractions (GMCs) with defecations in 75% of experiments in neurally intact dogs. These effects were inhibited by atropine, hexamethonium, ondansetron, and HC-030031 but unaltered by capsazepine. In dogs with T/R, the increase in colonic motility was inhibited in the middle-distal colon. In dogs with extrinsic denervation, the increase in colonic motility in the distal colon was decreased. CONCLUSIONS: Intracolonic AITC stimulates colonic motility and defecation via cholinergic, serotonergic, and TRPA1 pathways. Continuity of colonic enteric neurons plays an essential role in the intracolonic AITC-induced colonic motor response, while extrinsic nerves are important in occurrence and propagation of GMCs.
Assuntos
Colo/efeitos dos fármacos , Defecação/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Isotiocianatos/farmacologia , Canais de Potencial de Receptor Transitório/agonistas , Acetanilidas/farmacologia , Anastomose Cirúrgica , Animais , Atropina/farmacologia , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Colo/inervação , Colo/fisiologia , Colo/cirurgia , Denervação , Cães , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/fisiologia , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Íleo/inervação , Isotiocianatos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Ondansetron/farmacologia , Purinas/farmacologia , Antagonistas da Serotonina/farmacologiaRESUMO
The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a "floxed" ERα transgenic mouse line (ERα(flox)) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERα(flox) mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα(-) mice or Ad-Cre-injected ERα(flox) mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα(-) mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.
Assuntos
Angiotensina II , Pressão Sanguínea , Receptor alfa de Estrogênio/deficiência , Técnicas de Silenciamento de Genes , Hipertensão/metabolismo , Órgão Subfornical/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Feminino , Bloqueadores Ganglionares/farmacologia , Genótipo , Frequência Cardíaca , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Masculino , Camundongos Knockout , Nestina/genética , Nestina/metabolismo , Fenótipo , Órgão Subfornical/fisiopatologia , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologiaRESUMO
OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 ± 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 ± 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20% (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and ~50% of stress-activated neurons in these regions also expressed GABAA receptors and ~45% were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.
Assuntos
Hipertensão/etiologia , Receptores de GABA-A/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Diazepam/administração & dosagem , Moduladores GABAérgicos/administração & dosagem , Bloqueadores Ganglionares/farmacologia , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos , Neuropeptídeo Y/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Tartarato de Pentolínio/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Restrição Física , Estresse FisiológicoRESUMO
We hypothesize that a local ATP-NO-NMDA glutamate receptor interaction in the paraventricular nucleus (PVN) modulates the baseline mean arterial pressure and heart rate in unanaesthetized rats. The microinjection of α,ß-methylene ATP [methyl ATP; 0.06, 0.12 and 1.2 nmol (100 nl)(-1)] into the PVN caused pressor and tachycardiac responses. Cardiovascular responses evoked by methyl ATP [0.12 nmol (100 nl)(-1)] in the PVN were blocked by pretreatment with the ganglion blocker pentolinium (5 mg kg(-1) i.v.). Also, responses to the injection of methyl ATP [0.12 nmol (100 nl)(-1)] into the PVN were reduced by pretreatment with the selective P2 purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid [0.5 nmol (100 nl)(-1)], the neuronal NO synthase inhibitor N(ω)-propyl-l-arginine [0.04 nmol (100 nl)(-1)] or the selective NMDA glutamate receptor antagonist LY235959 [2 nmol (100 nl)(-1)]. In addition, an injection of the NO donor sodium nitroprusside [27 nmol (100 nl)(-1)] into the PVN caused similar cardiovascular responses to those observed after methyl ATP, which were blocked by local pretreatment with LY235959. Therefore, the present results suggest that cardiovascular responses evoked by methyl ATP in the PVN involve a local production of NO, which promotes local glutamate release and activation of NMDA receptors that are probably located in pre-autonomic parvocellular neurons, leading to sympathetic nervous system stimulation.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Óxido Nítrico/fisiologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Trifosfato de Adenosina/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microinjeções , Óxido Nítrico/biossíntese , Nitroprussiato/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Quinazolinonas , Ratos , Ratos Wistar , VigíliaRESUMO
BACKGROUND: Cigarette smoking is associated with symptomatic vasospasm after subarachnoid hemorrhage (SAH). METHODS: Rat basilar arteries of a normal group and SAH groups (1 hour, 2 days, and 1 week) were removed from the brain and cut into spiral preparations. RESULTS: A central nervous system (CNS) nicotinic acetylcholine receptor (nAChR) and autonomic ganglionic nAChR antagonist (mecamylamine) and skeletal muscle nAChR antagonist (gallamine) concentration-dependently attenuated the nicotine-induced contraction. An autonomic ganglionic nAChR antagonist (hexamethonium) did not affect nicotine-induced contractions in normal rats or rats with SAH. The various nAChR antagonists showed no significant differences in their effects between normal and SAH (1 hour, 2 days, and 1 week) rats. An L-type Ca(2+) channel antagonist (nifedipine) attenuated the nicotine-induced contraction in a concentration dependent manner. Inhibition by nifedipine was significantly enhanced in the 1-hour and 2-day SAH groups compared with normal and 1-week SAH groups. Levcromakalim showed a greater attenuation of nicotine-induced contraction in SAH (1 hour, 2 days, and 1 week) than in normal rats. CONCLUSIONS: Nicotine-induced contraction of the rat basilar artery involved the CNS nAChR subfamily, skeletal muscle nAChR subfamily, and L-type Ca(2+) channel pathways. SAH did not affect any of the subfamilies of nAChR, but the Ca(2+) channel was reduced and the adenosine triphosphate-sensitive K(+) channel was enhanced by SAH.
Assuntos
Artéria Basilar/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Canais KATP/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Hemorragia Subaracnóidea/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Artéria Basilar/metabolismo , Artéria Basilar/fisiopatologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Bloqueadores Ganglionares/farmacologia , Canais KATP/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/metabolismo , Hemorragia Subaracnóidea/fisiopatologiaRESUMO
Nicotine is the main active component of tobacco, and has both acute and chronic pharmacological effects that can contribute to its abuse potential in humans. The aim of the present study was to evaluate a possible role of GABA(B) receptors in acute and chronic responses to nicotine administration, by comparing GABA(B1) knockout mice and their wild-type littermates. In wild-type mice, acute nicotine administration (0.5, 1, 3 and 6 mg/kg, sc) dose-dependently decreased locomotor activity, and induced antinociceptive responses in the tail-immersion and hot-plate tests. In GABA(B1) knockout mice, the hypolocomotive effect was observed only with the highest dose of nicotine, and the antinociceptive responses in both tests were significantly reduced in GABA(B1) knockout mice compared to their wild-type littermate. Additionally, nicotine elicited anxiolytic- (0.05 mg/kg) and anxiogenic-like (0.8 mg/kg) responses in the elevated plus-maze test in wild-type mice, while selectively the anxiolytic-like effect was abolished in GABA(B1) knockout mice. We further investigated nicotine withdrawal in mice chronically treated with nicotine (25 mg/kg/day, sc). Mecamylamine (1 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type mice. However, signs of nicotine withdrawal were missing in GABA(B1) knockout mice. Finally, there was a decreased immunoreactivity of Fos-positive nuclei in the bed nucleus of the stria terminalis, basolateral amygdaloid nucleus and hippocampal dentate gyrus in abstinent wild-type but not in GABA(B1) knockout mice. These results reveal an interaction between the GABA(B) system and the neurochemical systems through which nicotine exerts its acute and long-term effects.
Assuntos
Estimulantes Ganglionares/toxicidade , Atividade Motora/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Receptores de GABA-B/metabolismo , Tabagismo/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/toxicidade , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/toxicidade , Ansiedade/induzido quimicamente , Comportamento Animal , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Relação Dose-Resposta a Droga , Bloqueadores Ganglionares/administração & dosagem , Bloqueadores Ganglionares/farmacologia , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/antagonistas & inibidores , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Nicotina/administração & dosagem , Nicotina/antagonistas & inibidores , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Limiar da Dor/efeitos dos fármacos , Receptores de GABA-B/genética , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Núcleos Septais/patologia , Tabagismo/metabolismoRESUMO
OBJECTIVE: Excessive opening of the adenosine triphosphate-sensitive potassium channel in vascular smooth muscle is implicated in the vasodilation and vascular hyporeactivity underlying septic shock. Therapeutic channel inhibition using sulfonylurea agents has proved disappointing, although agents acting on its pore appear more promising. We thus investigated the hemodynamic effects of adenosine triphosphate-sensitive potassium channel pore inhibition in awake, fluid-resuscitated septic rats, and the extent to which these responses are modulated by the high sympathetic tone present in sepsis. Temporal changes in ex-vivo channel activity and subunit gene expression were also investigated. DESIGN: In vivo and ex vivo animal study. SETTING: University research laboratory. SUBJECTS: Male adult Wistar rats. INTERVENTIONS AND MEASUREMENTS: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Pressor responses to norepinephrine and PNU-37883A (a vascular adenosine triphosphate-sensitive potassium channel inhibitor acting on the Kir6.1 pore-forming subunit) were measured at 6 or 24 hrs, in the absence or presence of the autonomic ganglion blocker, pentolinium. The aorta and mesenteric artery were examined ex vivo for rubidium efflux as a marker of adenosine triphosphate-sensitive potassium channel activity, and for adenosine triphosphate-sensitive potassium channel subunit gene expression using quantitative reverse transcription-polymerase chain reaction. MAIN RESULTS: A total of 120 rats (50 sham-operated controls, 70 septic) were included. Septic rats became hypotensive after 12 hrs, with a 24-hr mortality of 51.7% (0% in controls). At 6 hrs, there was an attenuated pressor response to norepinephrine (p < .01) despite blood pressure being elevated (p < .01). PNU-37883A had no pressor effect, except in the presence of pentolinium (p < .01). Kir6.1 subunit mRNA increased significantly in the mesenteric artery while rubidium efflux was increased in both the aorta and mesenteric artery at 24 hrs. CONCLUSIONS: Despite evidence of increased adenosine triphosphate-sensitive potassium channel activity in sepsis, it appears to be inhibited in vivo by high sympathetic tone. This may explain, at least in part, the reduced efficacy of adenosine triphosphate-sensitive potassium channel blockers in human septic shock.
Assuntos
Vasos Sanguíneos/fisiopatologia , Sepse/fisiopatologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Bloqueadores Ganglionares/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Morfolinas/farmacologia , Norepinefrina/farmacologia , Tartarato de Pentolínio/farmacologia , Ratos , Ratos Wistar , Sepse/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
AIMS: The role of the vagus in the ventricle is controversial, although the vagus can protect against ventricular fibrillation (VF) via nitric oxide (NO). This study aims to determine whether the mechanisms involved are dependent on post-ganglionic release and muscarinic receptor activation. For this purpose, NO release and electrophysiological effects of vagus nerve stimulation (VNS) were evaluated in relation to acetylcholine and vasoactive intestinal peptide (VIP). In addition, the role of the coronary endothelium and afferent nerves was tested. METHODS AND RESULTS: Using the isolated innervated rabbit heart, we measured ventricular NO release using 4,5-diaminofluorescein (DAF-2) fluorescence and ventricular fibrillation threshold (VFT) during VNS after muscarinic, ganglionic, and VIP inhibition [atropine, hexamethonium, and VIP (6-28), respectively] and after Triton-X endothelial functional dysfunction. The vagal-mediated increases in NO and VFT were not significantly affected (P> 0.05) during (i) atropine perfusion [increase in NO: 196.8 ± 35.2 mV (control) vs. 156.1 ± 20.3 mV (atropine) and VFT 3.1 ± 0.5 mA (control) vs. 2.7 ± 0.4 mA (atropine)], (ii) VIP inhibition-increase in NO: 243.0 ± 42.4 mV (control) vs. 203.9 ± 28.5 mV [VIP(6-28)] and VFT 3.3 ± 0.3 mA (control) vs. 3.9 ± 0.6 mA [VIP(6-28)], or (iii) after endothelial functional dysfunction [increase in NO: 127.7 ± 31.7 mV (control) vs. 172.1 ± 31.5 mV (Triton-X) and VFT 2.6 ± 0.4 mA (control) vs. 2.5 ± 0.5 mA (Triton-X)]. However, the vagal effects were inhibited during ganglionic blockade [increase in NO: 175.1 ± 38.1 mV (control) vs. 0.6 ± 25.3 mV (hexamethonium) and VFT 3.3 ± 0.5 mA (control) vs. -0.3 ± 0.3 mA (hexamethonium)]. CONCLUSIONS: We show that the vagal anti-fibrillatory action in the rabbit ventricle occurs via post-ganglionic efferent nerve fibres, independent of muscarinic receptor activation, VIP, and the endothelium. Together with our previous publications, our data support the possibility of a novel ventricular nitrergic parasympathetic innervation and highlight potential for new therapeutic targets to treat ventricular dysrhythmias.
Assuntos
Ventrículos do Coração/inervação , Miocárdio/metabolismo , Receptores Muscarínicos/metabolismo , Estimulação do Nervo Vago , Nervo Vago/fisiopatologia , Fibrilação Ventricular/prevenção & controle , Acetilcolina/metabolismo , Animais , Endotélio Vascular/metabolismo , Bloqueadores Ganglionares/farmacologia , Frequência Cardíaca , Masculino , Antagonistas Muscarínicos/farmacologia , Neurônios Nitrérgicos/metabolismo , Óxido Nítrico/metabolismo , Fibras Parassimpáticas Pós-Ganglionares/metabolismo , Fragmentos de Peptídeos/farmacologia , Coelhos , Receptores Muscarínicos/efeitos dos fármacos , Período Refratário Eletrofisiológico , Fatores de Tempo , Peptídeo Intestinal Vasoativo/metabolismo , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologia , Função VentricularRESUMO
BACKGROUND: R-type Ca(2+) channels are expressed by myenteric neurons in the guinea pig ileum but the specific function of these channels is unknown. METHODS: In the present study, we used intracellular electrophysiological techniques to determine the function of R-type Ca(2+) channels in myenteric neurons in the acutely isolated longitudinal musclemyenteric plexus. We used immunohistochemical methods to localize the Ca(V)2.3 subunit of the R-type Ca(2+) channel in myenteric neurons. We also studied the effects of the non-selective Ca(2+) channel antagonist, CdCl2 (100 µmol L⻹), the R-type Ca(2+) channel blockers NiCl2 (50 µmol L⻹) and SNX-482 (0.1 µmol L⻹), and the N-type Ca(2+) channel blocker x-conotoxin GVIA (CTX 0.1 µmol L⻹) on action potentials and fast and slow excitatory postsynaptic potentials (fEPSPs and sEPSPs) in S and AH neurons in vitro. KEY RESULTS: Ca(V)2.3 co-localized with calretinin and calbindin in myenteric neurons. NiCl2 and SNX-482 reduced the duration and amplitude of action potentials in AH but not S neurons. NiCl2 inhibited the afterhyperpolarization in AH neurons. x-conotoxin GVIA, but not NiCl2, blocked sEPSPs in AH neurons. NiCl2 and SNX-482 inhibited cholinergic, but not cholinergic/purinergic, fEPSPs in S neurons. CONCLUSIONS AND INFERENCES: These data show that R-type Ca(2+) channels contribute to action potentials, but not slow synaptic transmission, in AH neurons. R-type Ca(2+) channels contribute to release of acetylcholine as the mediator of fEPSPs in some S neurons. These data indicate that R-type Ca(2+) channels may be a target for drugs that selectively modulate activity of AH neurons or could alter fast synaptic excitation in specific pathways in the myenteric plexus.
Assuntos
Potenciais de Ação/fisiologia , Canais de Cálcio Tipo R/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Plexo Mientérico/citologia , Neurônios/fisiologia , Acetilcolina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cloreto de Cádmio/farmacologia , Calbindina 2 , Calbindinas , Bloqueadores dos Canais de Cálcio/farmacologia , Células Cultivadas , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Cobaias , Íleo/inervação , Masculino , Mecamilamina/farmacologia , Neurônios/efeitos dos fármacos , Níquel/farmacologia , Subunidades Proteicas/metabolismo , Proteína G de Ligação ao Cálcio S100/metabolismo , Venenos de Aranha/farmacologia , Transmissão Sináptica/fisiologia , ômega-Conotoxina GVIA/farmacologiaRESUMO
OBJECTIVES: Croton nepetaefolius is a medicinal plant useful against intestinal disorders. In this study, we elucidate the effects of its essential oil (EOCN) on sympathetic neurons, with emphasis on the interaction of EOCN- and histamine-induced effects. METHODS: The effects of EOCN and histamine were studied in guinea-pig celiac ganglion in vitro. KEY FINDINGS: Histamine significantly altered the resting potential (E(m)) and the input resistance (R(i)) of phasic neurons (from -56.6 +/- 1.78 mV and 88.6 +/- 11.43 MOmega, to -52.9 +/- 1.96 mV and 108.6 +/- 11.00 MOmega, respectively). E(m), R(i) and the histamine-induced alterations of these parameters were not affected by 200 microg/ml EOCN. The number of action potentials produced by a 1-s (two-times threshold) depolarising current and the current threshold (I(th)) for eliciting action potentials (rheobase) were evaluated. Number of action potentials and I(th) were altered by histamine (from 2.6 +/- 0.43 action potentials and 105.4 +/- 11.15 pA to 6.2 +/- 1.16 action potentials and 67.3 +/- 8.21 pA, respectively). EOCN alone did not affect number of action potentials and I(th) but it fully blocked the histamine-induced modifications of number of action potentials and I(th). All the effects produced by histamine were abolished by pyrilamine. CONCLUSIONS: EOCN selectively blocked histamine-induced modulation of active membrane properties.
Assuntos
Óleo de Cróton/farmacologia , Gânglios Simpáticos/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Óleos Voláteis/farmacologia , Potenciais de Ação , Animais , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacologia , Técnicas In Vitro , Cinética , Masculino , Pirilamina/farmacologiaRESUMO
AIM OF THE STUDY: Mentha piperita is a plant popularly known in Brazil as "hortelã-pimenta" whose essential oil is used in folk medicine for its anti-inflammatory, antispasmodic, expectorant actions and anti-congestive. Here, it was investigated the effect of Mentha piperita essential oil (peppermint oil) in rat tracheal rings along with its mechanism of action. MATERIALS AND METHODS: Tracheal tissue from male Wistar rats (250-300 g) were used. Peppermint oil was added in cumulative concentrations [1-300 microg/ml] to the tissue basal tonus or pre-contracted by carbachol [10 microM] at 10 min intervals, incubated or not with indomethacin [10 microM], L-N-metyl-nitro-arginine [100 microM], hexamethonium [500 microM], or tetraethylammonium [5 mM]. RESULTS: Peppermint oil [100 and 300 microg/ml] inhibited the contractions induced by carbachol, which was reversed by indomethacin, L-N-metyl-nitro-arginine and hexamethonium, but not by tetraethylammonium. These data suggest the participation of prostaglandin E(2), nitric oxide and autonomic ganglions in the peppermint oil relaxant effect and may be correlated with its popular use in respiratory diseases. CONCLUSIONS: Peppermint oil exhibited antispasmodic activity on rat trachea involving prostaglandins and nitric oxide synthase.
Assuntos
Mentha piperita , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Óleos de Plantas/farmacologia , Traqueia/efeitos dos fármacos , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Gânglios Autônomos/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Técnicas In Vitro , Masculino , Músculo Liso/inervação , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óleos de Plantas/química , Ratos , Ratos Wistar , Traqueia/inervação , Traqueia/metabolismoRESUMO
RATIONALE: Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases. OBJECTIVE: We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. METHODS AND RESULTS: Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart. CONCLUSIONS: These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.
Assuntos
Apoptose , Inativação Gênica , Insuficiência Cardíaca/enzimologia , Coração/inervação , Infarto do Miocárdio/enzimologia , Miocárdio/patologia , NADPH Oxidases/metabolismo , Núcleo Hipotalâmico Paraventricular/enzimologia , Sistema Nervoso Simpático/fisiopatologia , Adenoviridae/genética , Animais , Catalase/genética , Catalase/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Bloqueadores Ganglionares/farmacologia , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Hemodinâmica , Peróxido de Hidrogênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , NADPH Oxidase 4 , NADPH Oxidases/genética , Norepinefrina/urina , Oxirredução , Interferência de RNA , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
OBJECTIVE: We examined whether a specific increase in sympathetic nervous system (SNS) activity accounts for the enhanced depressor response to ganglion blockade in angiotensin II (AngII)-induced hypertension in rabbits or whether it reflects a general increased sensitivity of arterial pressure to vasodilatation. METHODS: Rabbits were renal denervated or sham-operated and 2 weeks later AngII (50 ng/kg per min) infusion commenced. Mean arterial pressure (MAP) responses to ganglion blockade (pentolinium) and vasodilators nitroprusside and adenosine were measured 2-4 weeks later. RESULTS: Basal MAP was 74 +/- 2 mmHg and maximum hypotensive responses to pentolinium, nitroprusside and adenosine were -17 +/- 2, -17 +/- 1 and -21 +/- 2 mmHg. AngII increased MAP similarly in intact and renal denervated rabbits (+25 +/- 4 mmHg and +31 +/- 4 mmHg, respectively). In intact rabbits, depressor responses to pentolinium were augmented by 75% during AngII infusion but responses to vasodilators also increased by 73-106% suggesting general augmentation of vascular reactivity rather than a specific increase in SNS neural activity. Consistent with this notion, total noradrenaline spillover was similar in normal and AngII-treated rabbits. In renal denervated rabbits, AngII enhanced depressor responses to vasodilators but not pentolinium, suggesting that sympathetic activity may be reduced by AngII hypertension when renal nerves are absent. In anaesthetized rabbits, methoxamine-induced decreases in hindlimb vascular conductance were greater in hypertensive than normotensive rabbits suggesting the presence of vascular hypertrophy of sufficient magnitude to explain increased responses to ganglion blockade and vasodilators. CONCLUSION: Enhanced depressor responses to ganglion blockade in AngII hypertension do not reflect augmented SNS activity, but rather, augmented sympathetic vasoconstriction mediated by a vascular amplifier effect.
Assuntos
Hipertensão/etiologia , Sistema Nervoso Simpático/fisiopatologia , Vasoconstrição , Adenosina/farmacologia , Angiotensina II , Animais , Pressão Sanguínea , Denervação , Bloqueadores Ganglionares/farmacologia , Membro Posterior/irrigação sanguínea , Hipertensão/sangue , Hipertensão/fisiopatologia , Rim/inervação , Nitroprussiato/farmacologia , Norepinefrina/sangue , Tartarato de Pentolínio/farmacologia , Coelhos , Fluxo Sanguíneo Regional , Resistência Vascular , Vasodilatadores/farmacologiaRESUMO
The present study tested the hypotheses that male and female rats respond differently to subcutaneous infusions of aldosterone (Aldo; 1.8 microg.kg(-1).h(-1), 1% NaCl to drink; 28 days) and that central estrogen plays a protective role against the development of hypertension. In rats with blood pressure (BP) and heart rate (HR) measured by Data Sciences International telemetry, chronic Aldo/NaCl treatment induced a greater increase in BP in males (Delta25.4 +/- 2.4 mmHg) than in females (Delta7.1 +/- 2.2 mmHg). Gonadectomy augmented Aldo/NaCl-induced hypertension in females (Delta18.2 +/- 2.0 mmHg) but had no effect in males (Delta23.1 +/- 2.9 mmHg). Immunohistochemistry for Fra-like activity was higher in the paraventricular nucleus of intact males, castrated males, and ovariectomized (OVX) females compared with intact females after 28 days of Aldo/NaCl treatment. In intact males, central 17beta-estradiol (E(2)) inhibited the Aldo/NaCl increase in BP (Delta10.5 +/- 0.8) compared with that in central vehicle plus systemic Aldo/NaCl (Delta26.1 +/- 2.5 mmHg) rats. Combined administration of E(2) and estrogen receptor antagonist ICI182780 (ICI) blocked the protective effect of E(2) (Delta23.2 +/- 2.4 mmHg). In intact females central, but not peripheral, infusions of ICI augmented the Aldo/NaCl (Delta20.4 +/- 1.8 mmHg) BP increase. Finally, ganglionic blockade after Aldo infusions resulted in a smaller reduction in BP in intact females (-23.9 +/- 2.5 mmHg) and in central estrogen-treated males (-30.2 +/- 1.0 mmHg) compared with other groups (intact males, -39.3 +/- 3.4; castrated males, -41.8 +/- 1.9; intact males with central E(2) + ICI, -42.3 +/- 2.1; OVX females, -40.3 +/- 3.3; and intact females with central ICI, -39.1 +/- 1.3 mmHg). Chronic Aldo infusion produced increases in NaCl intake and decreases in HR that were both similar in all groups. Taken together, the results indicate that central estrogen plays a protective role in the development of Aldo/NaCl-induced hypertension and that this may result from reduced sympathetic outflow.
Assuntos
Encéfalo/metabolismo , Estradiol/metabolismo , Hipertensão/prevenção & controle , Administração Oral , Aldosterona/administração & dosagem , Animais , Pressão Sanguínea , Peso Corporal , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Antagonistas de Estrogênios/administração & dosagem , Feminino , Fulvestranto , Bloqueadores Ganglionares/farmacologia , Frequência Cardíaca , Hexametônio/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Bombas de Infusão Implantáveis , Masculino , Orquiectomia , Ovariectomia , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Fatores Sexuais , Cloreto de Sódio/administração & dosagem , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Fatores de TempoRESUMO
Hyoscine butylbromide (HBB; tradenames: Buscopan/Buscapina is an antispasmodic drug for the treatment of abdominal pain associated with gastrointestinal cramping. As a hyoscine derivative, this compound competitively inhibits muscarinic acetylcholine (ACh) receptors on smooth muscle cells in the gastrointestinal tract. Preliminary investigations suggested that it might also inhibit nicotinic ACh receptors. This study investigated the effect of HBB on nicotinic ACh receptor-mediated membrane currents in SH-SY5Y cells. ACh and nicotine application-induced comparable membrane currents with EC(50) values of 25.9+/-0.6 and 40.1+/-0.4microM, respectively. When coapplied with 100microM ACh, HBB concentration-dependently suppressed currents with an IC(50) value of 0.19+/-0.04microM, and was approximately seven-times more potent than the ganglionic blocker, hexamethonium (IC(50)=1.3+/-0.3microM). Increasing the agonist concentration to 5mM did not affect the amount of block by HBB, which suggests a non-competitive mode of action. These functional in vitro data demonstrate for the first time that HBB blocks neuronal nicotinic ACh receptors in the same concentration range as it inhibits muscarinic ACh receptors. If one hypothesizes that HBB might also affect nicotinic receptors in autonomic neurons in vivo (e. g. in the enteric nervous system), this effect could contribute to its spasmolytic activity.