RESUMO
Hydrogen sulfide (H2S) is constitutively generated in the human body and works as a gasotransmitter in synaptic transmission. In this study, we aimed to evaluate the roles of endogenous H2S in generating eupnea at the respiratory center. We employed an in situ arterially perfused preparation of decerebrated rats and recorded the central respiratory outputs. When the H2S-producing enzyme cystathionine ß-synthase (CBS) was inhibited, respiration switched from the 3-phase eupneic pattern, which consists of inspiration, postinspiration, and expiration, to gasping-like respiration, which consists of inspiration only. On the other hand, when H2S synthesis was inhibited via cystathionine γ-lyase (CSE) or when H2S synthesis was activated via CBS, eupnea remained unchanged. These results suggest that H2S produced by CBS has crucial roles in maintaining the neuronal network to generate eupnea. The mechanism of respiratory pattern generation might be switched from a network-based system to a pacemaker cell-based system in low H2S conditions.
Assuntos
Sulfeto de Hidrogênio/metabolismo , Centro Respiratório/irrigação sanguínea , Centro Respiratório/metabolismo , Animais , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/inervação , Seio Carotídeo/metabolismo , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/metabolismo , Denervação , Ratos , Respiração , Centro Respiratório/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismoRESUMO
Recent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment.
Assuntos
Seio Carotídeo/inervação , Animais , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/fisiologia , Seio Carotídeo/anatomia & histologia , Seio Carotídeo/efeitos dos fármacos , Eletrodos Implantados , Feminino , Humanos , Condução Nervosa , Respiração , Cianeto de Sódio/farmacologia , SuínosRESUMO
BACKGROUND: We aimed to investigate whether the facilitating effect of H2S on the baroreceptor reflex is associated with the GABAA receptor, KATP channel and L-type Ca2+ channel pathway. METHODS: Spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were used to investigate the facilitating effect of H2S on the baroreceptor reflex by perfusing the isolated carotid sinus. The mechanism by which H2S facilitated the baroreceptor reflex was determined by using Bay K8644 (an agonist of calcium channels), glibenclamide (Gli, a KATP channel blocker), and picrotoxin (PIC, a blocker of γ-aminobutyric acid [GABA]A receptor). RESULTS: As compared with WKY rats, SHRs showed impaired baroreceptor reflex sensitivity, as demonstrated by a right and upward shift of the functional curve for the intrasinus pressure-arterial blood pressure relation. H2S perfusion (25, 50, or 100 µmol/L) dose-dependently ameliorated the impaired sensitivity of the baroreceptor reflex. Bay K8644 (500 nmol/L), Gli (20 µmol/L) and PIC (50 µmol/L) all prevented H2S ameliorating the impaired baroreceptor reflex. CONCLUSIONS: H2S facilitating the baroreceptor reflex might be associated with activating the GABAA receptor, opening the KATP channel, and closing the L-type Ca2+ channel. These areas should provide new targets for preventing and treating hypertension.
Assuntos
Barorreflexo/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Sulfeto de Hidrogênio/farmacologia , Hipertensão/fisiopatologia , Canais KATP/metabolismo , Receptores de GABA-A/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/metabolismo , Seio Carotídeo/fisiopatologia , Hipertensão/metabolismo , Masculino , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
AIMS: Rilmenidine and moxonidine are centrally acting antihypertensive agents that are more selective for I1-imidazoline receptors than for α2-adrenergic receptors. Moxonidine previously showed a peripheral vasoconstrictive effect stronger than generally recognized, which counteracted an arterial pressure (AP) lowering effect resulting from central sympathoinhibition. We tested whether rilmenidine also showed a significant vasoconstrictive effect that could attenuate its AP lowering effect. MAIN METHODS: Efferent sympathetic nerve activity (SNA) and AP responses to changes in carotid sinus pressure were compared in nine anesthetized Wistar-Kyoto rats before and after low, medium, and high doses (40, 100, and 250⯵g/kg, respectively) of intravenous rilmenidine. KEY FINDINGS: High-dose rilmenidine narrowed the range of the SNA response (from 89.6⯱â¯2.9% to 50.4⯱â¯7.9%, Pâ¯<â¯0.001) and reduced the lower asymptote of SNA (from 13.5⯱â¯3.0% to 2.7⯱â¯1.5%, Pâ¯<â¯0.001). High-dose rilmenidine significantly increased the intercept (from 57.1⯱â¯3.8 to 78.2⯱â¯2.7â¯mmâ¯Hg, Pâ¯<â¯0.001) but reduced the slope (from 0.82⯱â¯0.08 to 0.51⯱â¯0.07â¯mmâ¯Hg/%, Pâ¯<â¯0.001) of the SNA-AP relationship. The reduction in the operating-point AP induced by high-dose rilmenidine did not significantly differ based on whether the peripheral effect was considered (-19.8⯱â¯2.2 vs. -26.4⯱â¯5.3â¯mmâ¯Hg, not significant). SIGNIFICANCE: Rilmenidine increased AP in the absence of SNA, which suggests a peripheral vasoconstrictive effect; however, the vasoconstrictive effect was weak and did not significantly counteract the AP-lowering effect through central sympathoinhibition.
Assuntos
Anti-Hipertensivos/farmacologia , Barorreflexo/efeitos dos fármacos , Rilmenidina/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/fisiologia , Masculino , Ratos , Ratos Endogâmicos WKY , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/fisiologiaRESUMO
AIMS: Moxonidine is a centrally acting antihypertensive agent with a selectivity to I1-imidazoline receptors higher than that to α2-adrenergic receptors. The present study aimed to quantify a peripheral effect of moxonidine on carotid sinus baroreflex-mediated sympathetic arterial pressure (AP) regulation separately from its central effect. MAIN METHODS: In eight anesthetized Wistar rats, changes in efferent sympathetic nerve activity (SNA) and AP in response to a carotid sinus pressure input were compared before and during an intravenous administration of moxonidine (100µgkg-1 bolus followed by a continuous infusion at 200µg·kg-1·h-1). KEY FINDINGS: Moxonidine significantly narrowed the range of the AP response (55.3±5.8 to 39.1±6.1mmHg, P<0.05) without changing the minimum AP (77.2±6.4 to 80.7±5.1mmHg, not significant). In the neural arc, moxonidine reduced the minimum SNA (56.6±5.9 to 29.7±6.2%, P<0.05) without affecting the range of the SNA response (45.3±5.5 to 40.2±5.0%, not significant). In the peripheral arc, moxonidine increased the intercept (3.0±8.5 to 51.1±7.2mmHg, P<0.01) and reduced the slope (1.28±0.06 to 0.92±0.15mmHg/%, P<0.05). SIGNIFICANCE: Moxonidine increased AP at any given SNA, suggesting that the peripheral vasoconstrictive effect is stronger than generally recognized. The peripheral vasoconstrictive effect of moxonidine may partly offset the vasodilatory effect attained by centrally-mediated sympathoinhibition.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Imidazóis/farmacologia , Animais , Seio Carotídeo/metabolismo , Imidazóis/administração & dosagem , Infusões Intravenosas , Injeções Intravenosas , Masculino , Ratos , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: We aimed to investigate the regulatory effects of hydrogen sulfide (H2S) on carotid sinus baroreceptor sensitivity and its mechanisms. METHODS AND RESULTS: Male Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) were used in the experiment and were given an H2S donor or a cystathionine-ß-synthase inhibitor, hydroxylamine, for 8 weeks. Systolic blood pressure and the cystathionine-ß-synthase/H2S pathway in carotid sinus were detected. Carotid sinus baroreceptor sensitivity and the functional curve of the carotid baroreceptor were analyzed using the isolated carotid sinus perfusion technique. Effects of H2S on transient receptor potential cation channel subfamily V member 1 (TRPV1) expression and S-sulfhydration were detected. In SHRs, systolic blood pressure was markedly increased, but the cystathionine-ß-synthase/H2S pathway in the carotid sinus was downregulated in comparison to that of Wistar-Kyoto rats. Carotid sinus baroreceptor sensitivity in SHRs was reduced, demonstrated by the right and upward shift of the functional curve of the carotid baroreceptor. Meanwhile, the downregulation of TRPV1 protein was demonstrated in the carotid sinus; however, H2S reduced systolic blood pressure but enhanced carotid sinus baroreceptor sensitivity in SHRs, along with TRPV1 upregulation in the carotid sinus. In contrast, hydroxylamine significantly increased the systolic blood pressure of Wistar-Kyoto rats, along with decreased carotid sinus baroreceptor sensitivity and reduced TRPV1 protein expression in the carotid sinus. Furthermore, H2S-induced enhancement of carotid sinus baroreceptor sensitivity of SHRs could be amplified by capsaicin but reduced by capsazepine. Moreover, H2S facilitated S-sulfhydration of TRPV1 protein in the carotid sinus of SHRs and Wistar-Kyoto rats. CONCLUSIONS: H2S regulated blood pressure via an increase in TRPV1 protein expression and its activity to enhance carotid sinus baroreceptor sensitivity.
Assuntos
Barorreflexo , Pressão Sanguínea , Seio Carotídeo/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hipertensão/metabolismo , Pressorreceptores/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/fisiopatologia , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Sulfeto de Hidrogênio/administração & dosagem , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Mecanotransdução Celular , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/fisiopatologia , Processamento de Proteína Pós-Traducional , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/genéticaRESUMO
Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.
Assuntos
Seio Carotídeo/metabolismo , Células Quimiorreceptoras/metabolismo , Hipóxia/patologia , Estresse Oxidativo/fisiologia , Respiração , Acetofenonas/farmacologia , Alopurinol/farmacologia , Análise de Variância , Animais , Antiarrítmicos/farmacologia , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Dióxido de Carbono/metabolismo , Seio Carotídeo/efeitos dos fármacos , Catecolaminas/sangue , Células Quimiorreceptoras/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipóxia/fisiopatologia , Losartan/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Pletismografia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Análise de Regressão , Respiração/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologia , Fatores de Tempo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMO
BACKGROUND: The stability of an arterial baroreflex depends also upon the integrity of the afferent limb. For its quantification, we can use a noninvasive test such as baroreceptor sensitivity estimation during Valsalva manoeuvre. The aim of this study was to evaluate potential autonomic dysfunction in patients with unilateral severe carotid disease and compare the results to the results obtained from an age and gender matched group of healthy volunteers. METHODS: We evaluated dynamic changes during Valsalva manoeuvre (Valsalva ratio, cardiovagal and adrenergic baroreceptor sensitivity, sympathetic indexes and its dynamic ranges) in 41 patients (29 males; 62.9 ± 7.4 years) and compared the results to results obtained from volunteers (62.8 ± 7.0 years). RESULTS: Valsalva ratio between the patients and control group revealed no significant difference, as well as cardiovagal and adrenergic baroreceptor sensitivity. Sympathetic indexes, except for sympathetic index 2, reflecting the sympathetic vasoconstrictor baroreceptor response in late phase 2 of Valsalva manoeuvre (7.1 ± 13.1 mmHg in patients vs. 11.4 ± 10.2 mmHg in control group; p = 0.012) showed no significant differences between the studied groups. The most prominent dynamic range between the groups was within the sympathetic index 2. CONCLUSION: With some Valsalva manoeuvre test results, we were not able to show severe autonomic dysfunction in unilateral severe carotid stenosis patients except for lower vasoconstriction response within the late phase 2 of the manoeuvre.
Assuntos
Adrenérgicos/administração & dosagem , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo , Pressão Sanguínea , Estenose das Carótidas/fisiopatologia , Manobra de Valsalva , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/diagnóstico , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/fisiopatologia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIMS: To assess the acute effects of intravenous guanfacine, an α2A-adrenergic agonist, on sympathetic outflow from the central nervous system and on sympathetic arterial pressure (AP) response. MAIN METHODS: In anesthetized Wistar Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in electrical sympathetic nerve activity (SNA) and AP in response to a baroreceptor pressure input were examined before and after an intravenous administration of a high dose (100µg/kg, n=7) or a low dose (20µg/kg, n=5) of guanfacine. KEY FINDINGS: The higher dose of guanfacine significantly narrowed the range of the AP response (86.8±6.4 to 38.4±12.9mmHg, P<0.01) but increased the minimum AP (79.3±7.5 to 93.2±8.7mmHg, P<0.05). In the neural arc, guanfacine reduced both the response range (90.4±2.3 to 33.4±10.7%, P<0.01) and the minimum SNA (11.4±1.9 to 2.6±1.5%, P<0.01). In the peripheral arc, guanfacine increased the intercept (67.6±7.1 to 92.8±8.5mmHg, P<0.01) without a significant effect on the slope. The lower dose of guanfacine weakened the effects on both the neural and peripheral arcs. SIGNIFICANCE: Guanfacine suppressed SNA without a significant reduction of AP, which may be attributable to the peripheral vasoconstrictive effect. Reducing the dose of acutely administered intravenous guanfacine does not aid in separating the central sympathoinhibitory effect from the peripheral vasoconstrictive effect on AP in anesthetized rats in vivo.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Pressão Arterial/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Guanfacina/administração & dosagem , Administração Intravenosa , Animais , Pressão Arterial/fisiologia , Pressão Arterial/efeitos da radiação , Barorreflexo/fisiologia , Seio Carotídeo/fisiologia , Masculino , Ratos , Ratos Endogâmicos WKY , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologiaRESUMO
Although oxidative redox signaling affects arterial pressure (AP) regulation via modulation of vascular tone and sympathetic nerve activity (SNA), it remains unknown which effect plays a dominant role in the determination of AP in vivo. Open-loop systems analysis of the carotid sinus baroreflex was conducted to separately quantify characteristics of the neural arc from baroreceptor pressure input to SNA and the peripheral arc from SNA to AP in normotensive Wistar-Kyoto (WKY; n = 8) and spontaneously hypertensive rats (SHR; n = 8). Responses in SNA and AP to a staircase-wise increase in carotid sinus pressure were examined before and during intravenous administration of the membrane-permeable superoxide dismutase mimetic tempol (30 mg/kg bolus followed by 30 mg·kg(-1)·h(-1)). Two-way ANOVA indicated that tempol significantly decreased the response range of SNA (from 89.1 ± 2.4% to 60.7 ± 2.5% in WKY and from 77.5 ± 3.2% to 56.9 ± 7.3% in SHR, P < 0.001) without affecting the lower plateau of SNA (from 12.5 ± 2.4% to 9.5 ± 2.5% in WKY, and from 28.8 ± 2.8% to 30.4 ± 5.7% in SHR, P = 0.800) in the neural arc. While tempol did not affect the peripheral arc characteristics in WKY, it yielded a downward change in the regression line of AP vs. SNA in SHR. In conclusion, oxidative redox signaling plays an important role, not only in the pathological AP elevation, but also in the baroreflex-mediated physiological AP regulation. The effect of modulating oxidative redox signaling on the peripheral arc contributed to the determination of AP in SHR but not in WKY.
Assuntos
Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Barorreflexo/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Óxidos N-Cíclicos/farmacologia , Hipertensão/tratamento farmacológico , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Seio Carotídeo/inervação , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de Sinais/efeitos dos fármacos , Marcadores de Spin , Sistema Nervoso Simpático/fisiopatologia , Fatores de TempoRESUMO
Phytoestrogens could offer multiple beneficial effects on the cardiovascular system. Here, we have examined the effects of coumestrol (CMT) on carotid baroreceptors activity (CBA) and the possible mechanisms in male rats. The functional parameters of carotid baroreceptors were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus. The levels of protein expression were determined by using ELISA and Western blotting. CMT (1 to 100µmolL(-1)) inhibited CBA, which shifted the functional curve of the carotid baroreceptor to the right and downward, with a marked decrease in the peak slope and the peak integral value of carotid sinus nerve discharge in a concentration dependent manner. These effects were not blocked by a specific estrogen receptor antagonist ICI 182,780, but were completely abolished by nitric oxide (NO) synthase inhibitor l-NAME (N(G)-nitro-l-arginine methyl ester). Furthermore, a NO donor, SIN-1(3-morpholion-sydnon-imine), could potentiate these inhibitory effects of CMT. CMT stimulated the phosphorylation of Ser(1176)-eNOS (endothelial nitric oxide synthase) in a dose-dependent manner in carotid bifurcation tissue over a perfusion period of 15min. The rapid activation of eNOS by CMT was blocked by a highly selective PKA (protein kinase A) inhibitor H89. In addition, inhibition of PI3K (phosphatidylinositol-3-kinase) and ERK (extracellular signal-regulated kinase) pathways had no effect on eNOS activation by CMT. CMT inhibited CBA via eNOS activation and NO synthesis. These effects were mediated by the cAMP/PKA pathway and were unrelated to the estrogenic effect.
Assuntos
Seio Carotídeo/metabolismo , Cumestrol/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , AMP Cíclico/fisiologia , Óxido Nítrico/metabolismo , Pressorreceptores/metabolismo , Anestesia/métodos , Animais , Seio Carotídeo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Técnicas de Cultura de Órgãos , Pressorreceptores/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Arterial pressure (AP) elevates as a logarithmic function of exogenously administered dose of norepinephrine (NE). In contrast, AP is nearly linearly correlated with efferent sympathetic nerve activity (SNA) during acute baroreflex intervention. The present study aimed at quantifying the relationship between SNA and plasma NE concentration during acute baroreflex intervention. Carotid sinus regions were isolated from systemic circulation in five Wistar Kyoto rats, and carotid sinus pressure was changed among 60, 100, 120, 140, and 180 mm Hg every 2 min. Arterial blood (0.2 ml) was obtained at each pressure level for plasma NE measurement. Maximum AP and minimum AP were 153.34 ± 6.28 and 67.31 ± 4.92 mm Hg, respectively, in response to pressure perturbation. Plasma NE correlated linearly with SNA for individual animal data (slope: 0.957 ± 0.090 pg · ml(-1) · %(-1), intercept: 46.57 ± 7.22 pg/ml, r(2): ranged from 0.923 to 0.992) and also for group averaged data (NE = 0.956 × SNA + 47.97, r(2 )= 0.982). Blockade of neuronal NE uptake by intravenous desipramine (1 mg/kg) administration increased the slope (2.966 ± 0.686 pg · ml(-1) · %(-1), P < 0.05) and the intercept (168.73 ± 28.53 pg/ml, P < 0.01) of the plasma NE-SNA relationship. These results indicate that the relationship between SNA and plasma NE concentration was nearly linear within the normal physiological range of acute baroreflex control of AP. While plasma NE concentration can reflect changes in SNA, it may also overestimate the sympathetic outflow from the central nervous system when neuronal NE uptake is impaired systemically.
Assuntos
Pressão Arterial/fisiologia , Barorreflexo/fisiologia , Seio Carotídeo/fisiologia , Norepinefrina/sangue , Nervos Esplâncnicos/fisiologia , Animais , Pressão Arterial/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Seio Carotídeo/efeitos dos fármacos , Desipramina/farmacologia , Modelos Lineares , Masculino , Ratos Endogâmicos WKY , Nervos Esplâncnicos/efeitos dos fármacosRESUMO
Our laboratory has demonstrated that the cardiomotor component of aortic baroreflex is temporarily inhibited at the onset of spontaneous motor activity in decerebrate cats, without altering carotid sinus baroreflex. A reason for this dissociation may be attributed to a difference in the responses between aortic nerve activity (AoNA) and carotid sinus nerve activity (CsNA) during spontaneous motor activity. The stimulus-response curves of AoNA and CsNA against mean arterial blood pressure (MAP) were compared between the pressor interventions evoked by spontaneous motor activity and by intravenous administration of phenylephrine or norepinephrine, in which the responses in heart rate (HR) were opposite (i.e., tachycardia vs. baroreflex bradycardia), despite the identical increase in MAP of 34-40 mmHg. In parallel to the pressor response, mean AoNA and CsNA increased similarly by 78-81 and by 88 % of the baseline control, respectively, irrespective of whether the pressor response was evoked by spontaneous motor activity or by a pharmacological intervention. The slope of the stimulus-response curve of the mean AoNA became greater (P < 0.05) during spontaneous motor activity as compared to the pharmacological intervention. On the other hand, the stimulus-response curve of the mean CsNA and its slope were equal (P > 0.05) between the two pressor interventions. Furthermore, the slopes of the stimulus-response curves of both diastolic AoNA and CsNA (defined as the minimal value within a beat) exhibited a greater increase during spontaneous motor activity. All differences in the slopes of the stimulus-response curves were abolished by restraining HR at the intrinsic cardiac frequency. In conclusion, mean mass activities of both aortic and carotid sinus baroreceptors are able to encode the beat-by-beat changes in MAP not only at rest but also during spontaneous motor activity and spontaneous motor activity-related reduction of aortic baroreceptor activity is denied accordingly.
Assuntos
Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/fisiologia , Atividade Motora/fisiologia , Pressorreceptores/metabolismo , Seio Aórtico/efeitos dos fármacos , Seio Aórtico/fisiologia , Vasoconstritores/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Seio Carotídeo/metabolismo , Gatos , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Atividade Motora/efeitos dos fármacos , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Seio Aórtico/metabolismoRESUMO
Dynamic characteristics of arterial pressure (AP) regulation are important components in our understanding of rapid AP restoration by the arterial baroreflex system. The present study examined the effects of an L-type Ca(2+) channel blocker nifedipine on baroreflex-mediated dynamic AP regulation. In anesthetized and vagotomized rats, carotid sinus pressure was externally perturbed using a Gaussian white noise signal, and the neural arc transfer function from pressure input to efferent sympathetic nerve activity (SNA) and the peripheral arc transfer function from SNA to AP were identified. The peripheral arc transfer function approximated a second-order low-pass filter with pure dead time. Intravenous administration of nifedipine significantly decreased the steady-state gain and increased the damping ratio of the peripheral arc without affecting the dynamic characteristics of the neural arc. When the step response of AP was calculated based on the peripheral arc transfer function alone, nifedipine prolonged 80% rise time by 26%. When the closed-loop AP response was simulated based on both the neural arc and peripheral arc transfer functions and the dynamic gain of the baroreflex total loop was assumed to be 2.0, nifedipine prolonged 80% recovery time by 107%. In conclusion, L-type Ca(2+) channel blockade may compromise the baroreflex-mediated AP control not only in the magnitude but also in the speed of AP restoration.
Assuntos
Pressão Arterial/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Nifedipino/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/fisiologia , Avaliação Pré-Clínica de Medicamentos , Ratos , Ratos Endogâmicos WKYRESUMO
CONTEXT: Some anaesthetics exert an inhibitory effect on the response of the carotid body to low oxygen tension. However, the effect of dexmedetomidine on the carotid body response has not been reported. OBJECTIVE: To investigate the effect of dexmedetomidine on carotid body activity. The hypothesis is that dexmedetomidine does not have an inhibitory effect on the response of the carotid body to low oxygen tension. DESIGN: Animal experimental study in vitro. Ten carotid bodies surgically removed from male New Zealand white rabbits were tested. SETTING: Research laboratory of Nippon Medical School, Tokyo, Japan, from July 2008 to February 2010. INTERVENTION: The carotid body was perfused with three different concentrations of dexmedetomidine (0.1, 1.0 and 10 nmolâl). The contribution of α2-adrenergic receptors was evaluated by addition of 1.0 nmolâl yohimbine, an α2-adrenergic receptor antagonist. MAIN OUTCOME MEASURES: The differences in carotid sinus nerve activity between high oxygen tension (baseline) and low oxygen tension (peak) were analysed. RESULTS: At all three concentrations, dexmedetomidine did not depress the baseline and peak activity of the carotid body, whereas 0.1 nmolâl dexmedetomidine facilitated the response to low oxygen tension stimulation. The differences in carotid sinus nerve activity between baseline (pO2 80.4 ± 9.1 kPa) and peak (pO2 22.1 ± 2.6 kPa) were 140 ± 70 Hz in controls and 266 ± 116 Hz with 0.1 nM dexmedetomidine (P < 0.05). This increase was not shown in the presence of 1.0 nmolâl yohimbine. CONCLUSION: Dexmedetomidine does not depress the activity of the carotid body under high oxygen tension or the response to low oxygen tension, whereas 0.1 nmolâl dexmedetomidine facilitates this response via α2-adrenergic receptor activation.
Assuntos
Corpo Carotídeo/metabolismo , Dexmedetomidina/farmacologia , Oxigênio/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Potenciais de Ação , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos não Narcóticos/farmacologia , Anestésicos/farmacologia , Animais , Corpo Carotídeo/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Masculino , Coelhos , Transdução de Sinais/efeitos dos fármacos , Ioimbina/farmacologiaRESUMO
Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O2, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex and that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A(2B)) was down-regulated and that in petrosal ganglion (A(2A)) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.
Assuntos
Cafeína/farmacologia , Corpo Carotídeo/efeitos dos fármacos , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/metabolismo , Hipóxia/metabolismo , Aclimatação/efeitos dos fármacos , Adenosina/metabolismo , Animais , Cafeína/toxicidade , Corpo Carotídeo/metabolismo , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/inervação , Seio Carotídeo/metabolismo , Dopamina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Cistos Glanglionares/metabolismo , Hipercapnia/metabolismo , Hiperventilação/metabolismo , Pressão Parcial , Ventilação Pulmonar/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Purinérgicos P1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Lavender plants have been used for their cosmetic and biologic benefits for many centries. Extracts from Lavandula plants have been found to cause antimuscarinic effects by blocking sodium and calcium ion channels in in vitro and in vivo studies. We present a case of poisoning by ingestion of tea made from Lavender stoechas ( grass). The patient was admitted to our emergency department with supraventricular tachycardia due to anticholinergic syndrome triggered by drinking lavender tea. On electrocardiography, a narrow QRS complex tachycardia was evident. After carotid sinus massage, the patient immediately returned to sinus rhythm. There are no reported data about the toxicity of Lavender stoechas plants with respect to supraventricular tachycardia, anticholinergic syndrome or sympathetic nerve activity.
Assuntos
Antagonistas Colinérgicos/intoxicação , Lavandula , Taquicardia Supraventricular/induzido quimicamente , Chá/intoxicação , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/fisiopatologia , Eletrocardiografia , Feminino , Humanos , Pessoa de Meia-Idade , Taquicardia Supraventricular/fisiopatologiaRESUMO
OBJECTIVE: Chronic carotid baroreflex stimulation (Rheos system) has been shown to effectively reduce blood pressure in patients with resistant hypertension. Upon acute stimulation blood pressure also falls as a function of voltage. the aim of this study is to evaluate whether this voltage-dependent blood pressure decrease is preserved after long-term carotid baroreflex stimulation. METHODS: Forty-five patients implanted with Rheos underwent a voltage response test (VRT) before the start of carotid baroreflex activation (1m), as well as after 4 (4m) and 13 months (13 m) of device implantation. After switching off the device for 10 min (0âV), we started the VRT by increasing voltage from 1 to 6 V, by 1-V steps every 5 min. Blood pressure and heart rate were measured at the end of every step. RESULTS: At 1m, mean blood pressure was 178/101 mmHg at 0 V and fell to 142/83 mmHg at 6 V. Heart rate fell from 75 to 65 beats/min. At 4m and 13 m mean blood pressure was significantly lower compared to 1m when VRT started at 0 V (170/96 and 161/93 mmHg, respectively). However, pattern of blood pressure decrease during VRT was comparable with this at 1m. Maximum SBP reduction during VRT did not change with long-term therapy. CONCLUSIONS: Acute voltage-dependent blood pressure and heart rate decrease with electrical baroreflex stimulation is preserved after at least 1 year of continuous activation in patients with resistant hypertension. This indicates that response adaptation and nerve fatigue are very unlikely in long-term carotid baroreflex activation.
Assuntos
Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Seio Carotídeo/fisiopatologia , Terapia por Estimulação Elétrica/métodos , Hipertensão/terapia , Pressorreceptores/fisiopatologia , Anti-Hipertensivos/uso terapêutico , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Resistência a Medicamentos , Eletrodos Implantados , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pressorreceptores/efeitos dos fármacos , Estudos ProspectivosRESUMO
Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O(2)) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O(2)) and in response to hypoxias of different intensities (10, 5, and 2% O(2)) to study the release pathways. We found that ZM241385, an A(2) antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 30.8 and 72.5%, respectively. Suramin, a P(2)X antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O(2) levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia.
Assuntos
Trifosfato de Adenosina/metabolismo , Adenosina/metabolismo , Corpo Carotídeo/metabolismo , Células Quimiorreceptoras/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , Animais , Cálcio/metabolismo , Corpo Carotídeo/efeitos dos fármacos , Seio Carotídeo/efeitos dos fármacos , Seio Carotídeo/metabolismo , Células Quimiorreceptoras/efeitos dos fármacos , Feminino , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Neurotransmissores/metabolismo , Oxigênio/administração & dosagem , Antagonistas de Receptores Purinérgicos P1/farmacologia , Ratos , Ratos Wistar , Receptores Purinérgicos P2/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
Resistant hypertension is a prevalent dilemma. Despite all available antihypertensive medications and multiple strategies such as healthier diets and exercise programs, many patients are still unable to maintain or reach a therapeutic goal for systolic blood pressure. Because of this major health concern, CVRx, Inc has developed a treatment involving baroreflex activation therapy (Rheos Baroreflex Hypertension Therapy System) to treat patients with uncontrolled high blood pressure. The surgical implantation of this system is similar to a carotid endarterectomy procedure; however, the anesthetic management for this procedure is unique and challenging. This case report describes a 45-year-old African American woman with a history of hypertension who was receiving multiple antihypertensive medications and, thus, was a qualified candidate for implantation of this device. The goal of anesthetic management during implantation of this hypertension therapy system is to preserve the carotid sinus baroreceptor sensitivity by avoiding administering anesthetic agents that inhibit the baroreceptor reflex during electrode placement and the testing period. Because of the restriction of some of the anesthetic agents that an anesthesia provider can use, this procedure poses major challenges to the anesthesia provider in planning for anesthesia care and managing risks to the patient.