ASIC2 Synergizes with TRPV1 in the Mechano-Electrical Transduction of Arterial Baroreceptors / 神经科学通报·英文版

Mechanosensitive ion channels (MSCs) are key molecules in the mechano-electrical transduction of arterial baroreceptors. Among them, acid-sensing ion channel 2 (ASIC2) and transient receptor potential vanilloid subfamily member 1 (TRPV1) have been studied extensively and documented to play important roles. In this study, experiments using aortic arch-aortic nerve preparations isolated from rats revealed that both ASIC2 and TRPV1 are functionally necessary, as blocking either abrogated nearly all pressure-dependent neural discharge. However, whether ASIC2 and TRPV1 work in coordination remained unclear. So we carried out cell-attached patch-clamp recordings in HEK293T cells co-expressing ASIC2 and TRPV1 and found that inhibition of ASIC2 completely blocked stretch-activated currents while inhibition of TRPV1 only partially blocked these currents. Immunofluorescence staining of aortic arch-aortic adventitia from rats showed that ASIC2 and TRPV1 are co-localized in the aortic nerve endings, and co-immunoprecipitation assays confirmed that the two proteins form a compact complex in HEK293T cells and in baroreceptors. Moreover, protein modeling analysis, exogenous co-immunoprecipitation assays, and biotin pull-down assays indicated that ASIC2 and TRPV1 interact directly. In summary, our research suggests that ASIC2 and TRPV1 form a compact complex and function synergistically in the mechano-electrical transduction of arterial baroreceptors. The model of synergism between MSCs may have important biological significance beyond ASIC2 and TRPV1.

Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes / 神经科学通报·英文版

Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes. Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances (such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.

Paciente con hipertensión arterial y deterioro de su clase funcional secundarios al síndrome de taquicardia postural ortostática / Patient with arterial hypertension and functional class deterioration secondary to postural orthostatic tachycardia syndrome

Resumen La hipertensión ortostática ha sido un diagnóstico elusivo en la práctica clínica por la falta de estudio respecto a su fisiopatología y epidemiología. De esa manera, el abordaje clínico no ha sido expedito para su diagnóstico y tratamiento, así que las causas primarias pueden pasar inadvertidas y sin tratamiento. Se expone el caso clínico de una paciente latina, con hipertensión arterial sumada a deterioro de su clase funcional, a quien se le descartaron otras causas secundarias de hipertensión, y se diagnosticó, mediante estudio hemodinámico y autonómico, síndrome de taquicardia ortostática postural y compromiso del retorno venoso como causa primaria. Este reporte de caso pretende ilustrar respecto a esta causa infrecuente de hipertensión secundaria.

Abstract Orthostatic hypertension has been an elusive diagnosis in clinical practice due to the lack of research with regards to its pathophysiology and aetiology. Thus, clinical approach has not been unobstructed for its diagnosis and treatment, so the primary causes may go unnoticed and remain untreated. The clinical case of a Latin American patient with arterial hypertension associated to a deterioration of her functional class is reported. Secondary causes for hypertension were ruled out and, by means of a hemodynamic and autonomic study, she was diagnosed with postural orthostatic tachycardia syndrome and reduced venous return as the primary cause. This case report pretends to illustrate this rare case of secondary hypertension.

Modelado de los barorreceptores de baja presión y su contribución al control de la presión arterial / Modeling low pressure baroreceptors and their contribution to blood pressure control / Modelado dos barorreceptores de baixa pressão e sua contribuição ao controle da pressão arterial

El principal mecanismo de control de la presión arterial (PA) lo coordina el sistema nervioso central por medio del simpático y el parasimpático. Para simular este mecanismo existen diferentes modelos matemáticos que solo consideran los presorreceptores (barorreceptores) de alta presión, como mecanismo sensor de la PA. Sin embargo, existen otros receptores ubicados en las zonas de baja presión, que, hasta donde sabemos, no han sido considerados en los modelos descritos en la literatura, aunque tienen una participación importante en el control nervioso de la PA. Este artículo presenta un modelo matemático para la representación de los presorreceptores (barorreceptores) de baja presión, mediante la detección de los cambios delvolumen sanguíneo en la aurícula, y su aporte al control inmediato de la PA, mediante la estimulación nerviosa de la frecuencia cardíaca. El modelo propuesto se acopló al mecanismo sensor de un modelo mayor. A partir del modelo es posible analizar la contribución y el comportamiento de los receptores de baja presión, lo que permite entender mejor este complejo sistema tanto en condiciones normales como patológicas, al incluir variables importantes en el control inmediato de la PA, que no se han incluido en modelos anteriores.

The main mechanism for blood pressure (BP) control is coordinated by the central nervous system through the sympathetic and parasympathetic systems. In order to simulate this mechanism, different mathematical models are available, but they take into account only the high pressure receptors as sensing systems for BP. However, other receptors located in low pressure areas have not, as far as we know, been considered in the models described in the literature, despite their important role in the nervous BP control. This paper presents a mathematical model for the representation of low pressure receptors by means of the detection of atrial volume changes, and their contribution to immediate BP control through nervous stimulation of the heart rate. The proposed model was coupled to the sensor mechanism of a larger model. With this model it is possible to analyze the contribution and behavior of low pressure receptors, thus allowing a better understanding of this complex system under normal and pathological conditions, since it includes important variables in the immediate BP control, not included in previous models.

O principal mecanismo de controle da pressão arterial (PA) o coordena o sistema nervoso central por meio do simpático e o parassimpático. Para simular este mecanismo existem diferentes modelos matemáticos que só consideram os pressorreceptores (barorreceptores) de alta pressão, como mecanismo sensor da PA. Mas, existem outros receptores localizados nas zonas de baixa pressão, que, até onde sabemos, não hão sido considerados nos modelos descritos na literatura, porém têm uma participação importante no controle nervoso da PA. Este artigo apresenta um modelo matemático para a reapresentação dos pressorreceptores(barorreceptores) de baixa pressão, mediante a detecção dos câmbios do volume sanguínea na aurícula, e seu aporte ao controle imediato da PA, mediante a estimulação nervosa da frequência cardíaca. O modelo proposto se acoplou ao mecanismo sensor de um modelo maior. A partir do modelo é possível analisar a contribuição e o comportamento dos receptores de baixa pressão, o que permite entender melhor este complexo sistema tanto em condições normais como patológicas, ao incluir variáveis importantes no controle imediato da PA, que não se hão incluído em modelos anteriores.

Pathways of Neurogenic and Humoral Control in the Vestibulosympathetic Reflex of Conscious Rats / 대한평형의학회지

OBJECTIVE: The vestibular system contributes control of blood pressure during postural changes through the vestibulosympathetic reflex. In the vestibulosympathetic reflex, afferent signals from the peripheral vestibular receptors are transmitted to the vestibular nuclei, rostral ventrolateral medullary nuclei, and then to the intermediolateral cell column of the thoracolumbar spinal cord. Physiological characteristics of the vestibulosympathetic reflex in terms of neurogenic and humoral control of blood pressure were investigated in this study. METHODS: Conscious rats with sinoaortic denervation were used for removal of baroreceptors in reflex control of blood pressure, and hypotension was induced by intravenous infusion of sodium nitroprusside (SNP). Expression of c-Fos protein was measured in the medial vestibular nuclei (MVN), rostral vestrolateral medullary nuclei(RVLM), and intermediolateral cell column (IMC) in T4-7, and levels of blood epinephrine were measured following SNP-induced hypotension. RESULTS: SNP-induced hypotension significantly increased expression of c-Fos protein in the MVN, RVLM, and IMC, also significantly increased level of blood epinephrine compared to normotensive control animals. CONCLUSION: These results suggest that the vestibulosympathetic reflex regulates blood pressure through neurogenic control including MVN, RVLM, and IMC, also through humoral control including epinephrine secretion by the adrenal medulla following SNP-induced hypotension. The physiological characteristics of the reflex may contribute to basic treatment of impairment of blood pressure control during postural changes.

Analysis of the Baroreceptor and Vestibular Receptor Inputs in the Rostral Ventrolateral Medulla following Hypotension in Conscious Rats

Input signals originating from baroreceptors and vestibular receptors are integrated in the rostral ventrolateral medulla (RVLM) to maintain blood pressure during postural movement. The contribution of baroreceptors and vestibular receptors in the maintenance of blood pressure following hypotension were quantitatively analyzed by measuring phosphorylated extracellular regulated protein kinase (pERK) expression and glutamate release in the RVLM. The expression of pERK and glutamate release in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) following hypotension induced by a sodium nitroprusside (SNP) infusion. The expression of pERK was significantly increased in the RVLM in the control group following SNP infusion, and expression peaked 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than seen in the control group. The SAD group showed a relatively higher reduction in pERK expression when compared with the BL group. The level of glutamate release was significantly increased in the RVLM in control, BL, SAD groups following SNP infusion, and this peaked 10 min after SNP infusion. The SAD group showed a relatively higher reduction in glutamate release when compared with the BL group. These results suggest that the baroreceptors are more powerful in pERK expression and glutamate release in the RVLM following hypotension than the vestibular receptors, but the vestibular receptors still have an important role in the RVLM.

Effect of Glutamate on the Vestibulo-Solitary Projection after Sodium Nitroprusside-Induced Hypotension in Conscious Rats

Orthostatic hypotension is most common in elderly people, and its prevalence increases with age. Attenuation of the vestibulo-sympathetic reflex (VSR) is commonly associated with orthostatic hypotension. In this study, we investigated the role of glutamate on the vestibulo-solitary projection of the VSR pathway to clarify the pathophysiology of orthostatic hypotension. Blood pressure and expression of both pERK and c-Fos protein were evaluated in the nucleus tractus solitarius (NTS) after microinjection of glutamate into the medial vestibular nucleus (MVN) in conscious rats with sodium nitroprusside (SNP)-induced hypotension that received baroreceptor unloading via sinoaortic denervation (SAD). SNP-induced hypotension increased the expression of both pERK and c-Fos protein in the NTS, which was abolished by pretreatment with glutamate receptor antagonists (MK801 or CNQX) in the MVN. Microinjection of glutamate receptor agonists (NMDA or AMPA) into the MVN increased the expression of both pERK and c-Fos protein in the NTS without causing changes in blood pressure. These results indicate that both NMDA and AMPA receptors play a significant role in the vestibulo-solitary projection of the VSR pathway for maintaining blood pressure, and that glutamatergic transmission in this projection might play a key role in the pathophysiology of orthostatic hypotension.

Efeito da terapêutica com beta-bloqueador na resposta dos quimiorreflexos e ergorreflexo em pacientes com insuficiência cardíaca / Effect of beta-blocker therapeutics on the chemoreflex and ergoreflex response in heart failure patients

A intolerância ao exercício físico na insuficiência cardíaca (IC) está relacionada a alterações hemodinâmicas e neurohumorais pela complexa interação dos reflexos cardiovasculares. Os quimiorreflexos central e periférico e o ergorreflexo estão envolvidos na hiperventilação de repouso e durante o exercício, contribuindo para intolerância ao esforço. Os objetivos do estudo foram avaliar o efeito da terapêutica com beta-bloqueador (betab) na resposta dos quimiorreflexos central e periférico e do ergorreflexo por meio das alterações da resposta ventilatória durante o teste de caminhada de seis minutos (T6M); e avaliar o efeito da sua otimização também sobre as catecolaminas plasmáticas e peptídeo natriurético do tipo B (BNP). Foram estudados 15 pacientes masculinos, 49.5 ± 2.5 anos, com diagnóstico de IC há mais de 3 meses, sem histórico de tratamento com betab, com fração de ejeção (FEVE) 25.9 ± 2.5%, classe funcional I-III (NYHA). Estes pacientes poderiam estar em uso de inibidores da enzima conversora da angiotensina, bloqueadores do receptor da angiotensina II e antagonista do receptor da aldosterona. Todos os indivíduos realizaram testes: ergoespirométrico em esteira segundo o protocolo de Naughton, três T6M em esteira com controle de velocidade pelo paciente randomizados (um com sensibilização dos quimiorreceptores centrais, um com sensibilização dos quimiorreceptores periféricos e um controle em ar ambiente - AA). Também realizaram T6M com e sem oclusão circulatória regional em membro inferior. Em relação aos exames laboratoriais, foram feitas análises de catecolaminas plasmáticas em repouso e BNP. Os pacientes foram então submetidos a tratamento medicamentoso padrão da Instituição, com introdução e otimização da terapêutica com ßb e, após seis meses, foram reavaliados. Após otimização do betab, houve melhora significativa na FEVE, de 26 ± 2,5 para 33 ± 2,6 (p < 0,05); diminuição de níveis de BNP (775 ± 163 para 257 ± 75; p < 0,01) e...

In heart failure (HF), exercise intolerance is related to hemodynamic and neurohumoral alterations by the complex interaction of cardiovascular reflexes. The central and peripheral chemoreflex and the ergoreflex are involved in hyperventilation at rest and during exercise, contributing to exercise intolerance. The aims of the study were to assess the effect of beta-blocker (betab) therapy on the central and peripheral chemoreflexes and ergoreflex responses through ventilatory changes during the six-minute walk test (6MWT), and to assess the effect of betab optimized therapy on plasma catecholamines and B-type natriuretic peptide (BNP). We studied 15 male patients, 49.5 ± 2.5 years, diagnosed with HF for more than three months, never-treated with ßb, ejection fraction (LVEF) 25.9 ± 2.5%, functional class I-III (NYHA). These patients could be in use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists. All subjects underwent the following tests: cardiopulmonary exercise treadmill test according to the Naughton protocol, three randomized treadmill 6MWT with speed controlled by the patient (one with sensitization of central chemoreceptors, one with an awareness of peripheral chemoreceptors and another control in ambiental air - AA). Also all subjects underwent 6MWT with and without regional circulatory occlusion on the lower limb. Regarding laboratory tests, plasma catecholamines concentration at rest and BNP were also analyzed. Patients were then submitted to the institution standard drug therapy, with introduction and optimization of betab and were reassessed six months later. After optimization, there was a significant improvement in LVEF from 26 ± 2.5 to 33 ± 2.6 (p < 0.05); and a decrease in BNP levels (775 ± 163 to 257 ± 75, p < 0.01) and plasma catecholamines (598 ± 104 to 343 ± 40, p < 0.05). There was also a significant decrease in resting heart rate from 95.6 ± 4.5 to 69.0 ± 1.6...

Controle neurovascular de corredores amadores hipertensos / Neurovascular control of hypertensive amateur runners

INTRODUÇÃO: Alterações neurovasculares presentes na hipertensão arterial são minimizadas pelo treinamento físico em hipertensos previamente sedentários. Entretanto, é desconhecido se atletas hipertensos apresentam alterações neurovasculares ou se o treinamento físico previne tais danos. Este estudo avaliou o controle neurovascular de corredores hipertensos, durante o treinamento competitivo, assim como o efeito de 4 meses de treinamento de intensidade moderada nesta população. MÉTODOS: 37 corredores, homens (20 normotensos, 43 +-1 anos e 17 hipertensos, 42+-1 anos), foram avaliados no treinamento competitivo e posteriormente divididos em 4 subgrupos: normotensos que mantiveram treinamento competitivo (n=10); normotensos que realizaram treinamento de intensidade moderada (n=10); hipertensos que mantiveram treinamento competitivo (n=8); hipertensos que realizaram treinamento de intensidade moderada (n=8). Após 4 meses de intervenção, todos os corredores foram novamente avaliados. Atividade nervosa simpática muscular (ANSM) (microneurografia), propriedades arteriais (velocidade da onda de pulso (VOP) e sistema echo-tracking de alta resolução), controle barorreflexo da frequência cardíaca (FC) e da ANSM (infusão de drogas vasoativas) foram avaliados. RESULTADOS: Corredores hipertensos apresentaram maior pressão arterial sistólica (P < 0,001), diastólica (PAD) (P < 0,001) e média (PAM) (P < 0,001) que corredores normotensos. A ANSM foi maior no grupo hipertenso (disparos/min.; P=0,02 e disparos/100 batimentos; P=0,004) em relação ao grupo normotenso. Não houve diferença na VOP (P=0,71) e nas variáveis da carótida: espessura intima-média (P=0,18), diâmetro (P=0,09) e distensão (P=0,79) entre os grupos. A equação sigmoidal para controle barorreflexo da FC, mostrou menor ganho barorreflexo nos corredores hipertensos em relação aos normotensos (resetting) (P=0,002). O controle barorreflexo da FC, avaliado pela análise de regressão linear, não foi...

INTRODUCTION: Neurovascular alterations presented in hypertension are minimized by physical training in previously sedentary hypertensive. However it is unknown if hypertensive athletes present neurovascular alterations or if physical training prevents these damages. This study evaluated the neurovascular control of hypertensive runners during competitive training as well as the effect of 4 months of moderate intensity training in this population. METHODS: 37 runners, male (20 normotensive, 43+-1 years old and 17 hypertensive, 42+-1 years old), were evaluated during competitive training and after that were divided in 4 subgroups: normotensive who maintained competitive training (n=10); normotensive who performed moderate intensity training (n=10); hypertensive who maintained competitive training (n=8); hypertensive who performed moderate intensity training (n=8). After 4 months of intervention, all the runners were evaluated again. Muscle sympathetic nerve activity (MSNA) (microneurography), arterial properties (pulse wave velocity (PWV) and high-resolution echo-tracking system), baroreflex control of heart rate (HR) and MSNA (infusion of vasoactive drugs) were evaluated. RESULTS: Hypertensive runners had higher systolic (P < 0.001), diastolic (DAP) (P < 0.001) and mean (MAP) (P < 0.001) arterial pressure than normotensive runners. MSNA was higher in hypertensive group (bursts/min.; P=0.02 and bursts/100 heart beats; P=0.004) than in normotensive group. There was no difference in PWV (P=0.71) and carotid variables: intima-media thickness (P=0.18), diameter (P=0.09) and distension (P=0.79) between groups. The gain of baroreflex control of HR, evaluated by sigmoidal logistic equation was lower in hypertensive runners than normotensive runners (resetting) (P=0.002). Baroreflex controf of HR, evaluated by linear equation analysis, was not different between groups during increase (slope P=0.41; intercept P=0.31) and decrease (slope P=0.16...

Effect of Vestibulosympathetic Reflex and Baroreflex on Expression of pERK in the Nucleus Tractus Solitarius following Acute Hypotension in Conscious Rats

Control of blood pressure is maintained by the interaction between the arterial baroreflex and vestibulosympathetic reflex during postural changes. In this study, the contributions of vestibular receptors and baroreceptors to the maintenance of blood pressure following acute hypotension were compared in terms of phosphorylated extracellular regulated protein kinase (pERK) expression in the nucleus tractus solitaries (NTS). Expression of pERK in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) 5, 10, 20, and 40 min following acute hypotension induced by sodium nitroprusside (SNP) infusion. Expression of pERK increased significantly in the NTS in the control group following SNP infusion, and the expression peaked at 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than in control group. The BL group showed a relatively higher reduction in pERK expression than the SAD group, and the pERK expression in the NTS was localized to the caudal portion of the nuclei in the BL and SAD groups. These results suggest that the vestibular receptors may play a key role in maintaining blood pressure following acute hypotension; thus, the vestibular system may contribute to compensate for orthostatic hypotension.

Effect on thermoregulatory responses in patients undergoing a tympanoplasty in accordance to the anesthetic techniques during PEEP: a comparison between inhalation anesthesia with desflurane and TIVA / 대한마취과학회지

BACKGROUND: It has been known that positive end-expiratory pressure (PEEP) increases the vasoconstriction threshold by baroreceptor unloading. We compared the effect on the thermoregulatory responses according to anesthetic techniques between an inhalation anesthesia with desflurane and a total intravenous anesthesia (TIVA) with propofol and reminfentanil when PEEP was applied in patients undergoing tympanoplasty. METHODS: Forty-six patients with a scheduled tympanoplasty were enrolled and the patients were divided in two study groups. Desflurane was used as an inhalation anesthetic in group 1 (n = 22), while TIVA with propofol and remifentanil was used in group 2 (n = 24). PEEP was applied by 5 cmH2O in both groups and an ambient temperature was maintained at 22-24degrees C during surgery. The core temperature and the difference of skin temperature between forearm and fingertip were monitored for about 180 minutes before and after the induction of general anesthesia. RESULTS: The final core temperature was significantly higher in group 2 (35.4 +/- 0.7degrees C) than in group 1 (34.9 +/- 0.5degrees C). Peripheral thermoregulatory vasoconstriction was found in 5 subjects (23%) in group 1 and in 21 subjects (88%) in group 2. The time taken for reaching the thermoregulatory vasoconstriction threshold was 151.4 +/- 19.7 minutes in group 1 and 88.9 +/- 14.4 minutes in group 2. CONCLUSIONS: When PEEP will be applied, anesthesia with TIVA may have more advantages in core temperature preservation than an inhalation anesthesia with desflurane.

Reflexo dos barorreceptores e homeostase da pressão arterial / Baroreflexes and blood pressure homeostasis

A hipertensão arterial é considerada um dos principais fatores de risco para a morbidade e mortalidade cardiovascular. Os reflexos originados nos barorreceptores arteriais e nos receptores de estiramento da região cardiopulmonar são os principais mecanismos de controle efetivo da pressão arterial a curto prazo. O reflexo dos barorreceptores é considerado um sistema de controle de alto ganho, que mantém a pressão arterial dentro de limites normais em períodos de segundos a minutos. Dessa forma, esta revisão busca abordar os mecanismos desenvolvidos pelos barorreceptores na homeostase da pressão arterial. No presente artigo foram relatadas as alterações dos reflexos cardiovasculares na hipertensão arterial, focando a distribuição dos barorreceptores e seu funcionamento no restabelecimento da pressão arterial. Para realização desta pesquisa foi realizada uma revisão de artigos científicos utilizando as bases de dados Medline, Scielo e Lilacs. Adicionalmente foram consultados livros de fisiologia humana para complementação das informações sobre a fisiologia do barorreflexo na homeostase da pressão arterial. Estudos clínicos têm mostrado que uma reduzida sensibilidade do barorreflexo está associada com a morte súbita que se segue ao infarto agudo do miocárdio. O entendimento dos reflexos dos barorreceptores e a manutenção da hipertensão arterial em curto prazo são de grande importância para o entendimento da fisiopatogenia envolvidas no desenvolvimento e/ou evolução de determinadas alterações patológicas (AU)

Hypertension is considered one of the main risk factors for cardiovascular morbidity and mortality. The reflexes of arterial baroreceptors and stretch receptors in the cardiopulmonary region are the primary mechanisms for effectively controlling arterial blood pressure in the short term. Baroreflexes are a relatively high gain control system that regulates blood pressure during short time periods such as seconds or minutes. This literature review aims to discuss the mechanisms developed by baroreceptors in blood pressure homeostasis. We describe the effects of cardiovascular reflexes on blood pressure, with focus on the distribution of baroreceptors and on its role in controlling blood pressure. Our research was based on scientific articles from the Medline, Scielo, and Lilacs databases. We also researched books on human physiology in order to describe the physiology of baroreflexes in blood pressure homeostasis. Clinical studies have shown that decreased baroreflex sensitivity is associated with sudden death following myocardial infarction. Understanding baroreflexes and short-term blood pressure regulation is essential for understanding the physiopathogenesis involved in the development of certain pathological changes (AU)

Involvement of cross interaction between central cholinergic and histaminergic systems in the nucleus tractus solitarius in regulating carotid sinus baroreceptor reflex / 生理学报

The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and possible modulatory mechanism of preceding microinjection with different histaminergic receptor antagonists, the selective histaminergic H1 receptor antagonist, i.e., chlorpheniramine (CHL) or the H2 receptor antagonist, i.e., cimetidine (CIM) into the NTS on the changes in function of CSR resulted from the i.c.v. cholinesterase inhibitor, physostigmine (PHY) were also examined in order to confirm and to analyze effects of cross interaction between central histaminergic and cholinergic systems on CSR. The main results obtained are as follows. (1) Standalone microinjection of different selective cholinergic receptor antagonists (PRZ, MTR or HEX) or different selective histaminergic receptor antagonists (CHL or CIM) into the NTS with each given dose had no effects on the CSR function and on the basic levels of the artery blood pressure, respectively (P > 0.05). (2) The pretreatment of PRZ or MTR into the NTS with each corresponding dose could attenuate CSR resetting resulted from i.c.v. HA in some degrees, which remarkably moved the posterior half range of ISP-MAP relationship curve downwards (P < 0.05), shifted the middle part of ISP-Gain relationship curve upwards (P < 0.05), and increased reflex parameters such as the MAP range and maximum gain (P < 0.05), but decreased parameters such as saturation pressure and intracarotid sinus pressure at maximum gain (P < 0.05). The catabatic effects of pretreatment with MTR into the NTS on CSR resetting induced by i.c.v. HA were more obvious than those with PRZ (P < 0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P > 0.05). (3) The effects of pretreatment of CHL or CIM into the NTS with each corresponding dose on CSR resetting made by i.c.v. PHY were similar to those of pretreatment of PRZ or MTR into the NTS on CSR resetting resulted from i.c.v. HA, and the decreasing effects of pretreatment with CHL into the NTS on CSR resetting induced by i.c.v. PHY were more remarkable than those with CIM (P < 0.05). These findings suggest that CSR resetting resulted from either HA or PHY into the lateral ventricle may partly involve the descending histaminergic or cholinergic pathway from the hypothalamus to NTS, which might evoke a cross activation of the cholinergic system in the NTS, via cholinergic M1 and M2 receptors mediation, especially the M2 receptors showing actions, or trigger another cross activation of the histaminergic system in the NTS, by histaminergic H1 and H2 receptors mediation, especially the H1 receptors displaying effects.

Improved methods for researching isolated carotid sinus baroreceptors automatically controlling for sinus pressure / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To develop a system for automatically controlling carotid sinus pressure in the study on baroreceptors.</p><p><b>METHODS</b>The preparation containing carotid sinus with parts of the connected vessels and carotid sinus nerve (CS-CSN) were isolated and perfused. A critical pressure controlling component (PRE-U, Hoerbiger, Deutschland) dictated by a computer was integrated into the system to clamp the intrasinus pressure. The pressure command and the relevant intrasinus pressure were compared to evaluate the validity of the pressure controlling system.</p><p><b>RESULTS</b>A variety of sinus pressure-controlling patterns, including pulsation, ramp and step pressures, could be achieved accurately by using the system, and the pressure-dependent discharge activities of sinus nerve were confirmed.</p><p><b>CONCLUSION</b>This system for clamping carotid sinus pressure could realize multiple pressure-controlling patterns and is a useful and flexible pressure controlling method that could applied in the study on mechano-electric transduction of baroreceptors.</p>

Depressed cardiac output at higher pacing rate in isolated working heart of rat / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To observe the regulation of heart rate to cardiac pump function in the phase of negative force-frequency relationship and their possible mechanisms.</p><p><b>METHODS</b>The left ventricular pressure, aortic pressure, and cardiac output were measured in isolated working heart of rat from 240 to 300 beats/min of pacing rate.</p><p><b>RESULTS</b>Cardiac output of isolated working heart was decreased by a proximally 20% (P < 0.01) with the increase in the pacing rate from 240 to 300 beats/min. Left ventricular end-systolic pressure (LVESP) was declined by 4.8% (P < 0.05), but left ventricular end-diastolic pressure (LVEDP) was elevated by 139% (P < 0.01) with an increase in the pacing rate. Left atrium was enlarged at 300 beats/min of pacing rate. The time from peak to 75% relaxation in left ventricular pressure was shortened with the increased pacing rate. Pressure at aortic valve close was raised (P < 0.01) and ejection duration was shortened with the increased pacing rate (P < 0.01).</p><p><b>CONCLUSION</b>Those above results suggest that there are different mechanisms between the depressed cardiac output at higher heart rate and negative force-frequency relationship. The frequency-dependent acceleration of relaxation facilitates the decline of left ventricular pressure, and then may elevate the pressure of aortic valve close in the condition that the shape of aortic pressure curve stays the same. Therefore, the ejection duration is shortened at higher pacing rate. The shortened ejection duration may induce a decrease in stroke volume of the left ventricle. The increment of heart rate is not enough to compensate the decreased stroke volume. Finally, cardiac output shows a decrease at higher heart rate.</p>

Additive Role of the Vestibular End Organ and Baroreceptors on the Regulation of Blood Pressure in Rats

Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM.

Electrical stimulation of deep peroneal nerve mimicking acupuncture inhibits the pressor response via capsaicin-insensitive afferents in anesthetized rats / 中国结合医学杂志

<p><b>OBJECTIVE</b>To assess the inhibitory modulation of blood pressure by stimulation of the deep peroneal nerve (DPN) and to determine the involvement of nociceptive fibers in the modulation.</p><p><b>METHODS</b>All the animals were divided into six groups (A-F). The rats in groups A and B received no pretreatment. The rats in groups C and D received subcutaneous injection of capsaicin or control vehicle, respectively, near the DPN for 2 days. Those in groups E and F had the DPN exposed to capsaicin or control vehicle, respectively, for 20 min. Subsequently, pressor responses were induced by stimulation of paraventricular nucleus (PVN) either electrically (groups A and C C-F) or chemically via injection of glutamate (group B). After two stable pressor responses (baseline), all groups were subject to 5-min DPN stimulation followed by PVN stimulation for 10 s. Arterial blood pressure, heart rate, and electrocardiogram were recorded. The pressor response was calculated as the difference in the mean arterial pressure (MAP) before and after PVN stimulation, and changes from baseline in pressor response after DPN stimulation were compared between the groups.</p><p><b>RESULTS</b>Increases of MAP of 22.88±2.18 mm Hg and 20.32±5.25 mm Hg were induced by electrical (group A) or chemical (group B) stimulation of the PVN, respectively. These pressor responses were inhibited by stimulation of the DPN, and the MAP was reduced to 12.00±2.10 mm Hg in group A (n=6, P<0.01) and 7.00±2.85 mm Hg in group B (n=6, P<0.01). Subcutaneous injection of capsaicin (125 mg/kg) near the DPN in group C (n=7) had no effect on the inhibitory effect of DPN stimulation compared with the group D (n=9), and neither did blockade of nociceptive fibers with capsaicin in group E (n=6) compared with group F (n=8).</p><p><b>CONCLUSION</b>Stimulation of the DPN mimicking acupuncture has an inhibitory effect on the pressor response, and the effect is mediated by capsaicin-insensitive afferent fibers in the DPN.</p>

Hyperperfusion Syndrome after Carotid Stent-Supported Angioplasty in Patients with Autonomic Dysfunction

Cerebral hyperperfusion syndrome (CHS) is a rare, serious complication of carotid revascularization either after carotid endarterectomy or carotid stent placement. Although extensive effort has been devoted to reducing the incidence of CHS, little is known about the prevention. Postprocedural hypertension is very rare due to autoregulation of carotid baroreceptors but may occur if presented with autonomic dysfunction. We present two cases of CHS after cerebral revascularization that presented autonomic dysfunction.

Comportamento do ergorreflexo na insuficiência cardíaca / Ergoreflex activity in heart failure / Comportamiento del ergorreflejo en la insuficiencia cardiaca

Grande número de evidências tem sugerido a existência de uma rede de reflexos que se tornam hiperativos secundariamente a alterações músculo-esqueléticas que ocorrem na síndrome insuficiência cardíaca (IC). Estes, aliados aos reflexos cardiovasculares simpato-inibitórios, suprimidos na síndrome, podem contribuir para a intolerância ao exercício físico. A hiperativação dos sinais originados dos receptores localizados nos músculos esqueléticos (mecanoceptores - metaborreceptores) é uma hipótese proposta recentemente para explicar a origem dos sintomas de fadiga e dispneia e os efeitos benéficos do treinamento físico na síndrome da IC. Na IC, outras alterações nos sistemas de controle reflexo, que não são mutuamente exclusivos, contribuem para dispneia. Estimulação inapropriada dos barorreceptores arteriais com consequente falta de inibição da descarga do metaborreflexo muscular e quimiorreflexo carotídeo e aumento da vasoconstricção renal com liberação de angiotensina II pode também ser considerada. Apesar das alterações funcionais dos reflexos terem sido usadas de maneira independente para ilustrar a excitação simpática observada na IC, a interação entre esses reflexos em condições normais e patológicas, especialmente sua contribuição para o estado simpato-excitatório encontrado na IC, não tem sido amplamente estudados. Assim, o problema se ambos os receptores musculares (mecano e metaborreceptores) estão envolvidos na gênese da exacerbação do ergorreflexo observado na IC ainda fica a ser resolvido. Dessa forma, essa revisão tem por objetivo integrar os conhecimentos a respeito do mecano e metaborreflexo (ergorreflexo) na síndrome da insuficiência cardíaca bem como esclarecer a influência da terapêutica medicamentosa da IC no ergorreflexo.

A large body of evidence has suggested the existence of a reflex network that becomes hyperactive secondary to musculoskeletal alterations that occur in heart failure (HF) syndrome. Together with sympathoinhibitory cardiovascular reflexes, suppressed in the presence of the syndrome, heart failure can contribute to physical exercise intolerance. The hyperactivation of signals originated from receptors located in skeletal muscles (mechanoreceptors - metaboreceptors) is a recently proposed hypothesis to explain the origin of fatigue and dyspnea symptoms in HF. In HF, other alterations in the reflex control system, which are not mutually exclusive, contribute to dyspnea. The inappropriate stimulation of the arterial baroreceptors, with the consequent lack of inhibition of the muscle metaboreflex and carotid chemoreflex unloading and the increase in the renal vasoconstriction with angiotensin II release can also be considered. Although the functional alterations of the reflexes were used independently to illustrate the sympathetic excitation observed in HF, the interaction between these reflexes under normal and pathological conditions, especially its contribution to the sympathoexcitatory state found in HF, has not been broadly investigated. Therefore, questions about a possible association between the muscle receptors (mechano and metaboreceptors) in the genesis of the ergoreflex exacerbation, observed in HF, remain. Thus, the objective of this review was to integrate the knowledge on the mechano and metaboreflex (ergoreflex) in HF syndrome, as well as to clarify the influence of HF drug therapy on the ergoreflex.

Gran número de evidencias viene sugerido la existencia de una red de reflejos que se hacen hiperactivos secundariamente a alteraciones musculoesqueléticas que se producen en el síndrome de la insuficiencia cardiaca (IC). Aliada a los reflejos cardiovasculares simpatoinhibitorios, suprimidos en el síndrome, la insuficiencia cardiaca puede contribuir a la intolerancia al ejercicio físico. La hiperactivación de los señales originados de los receptores ubicados en los músculos esqueléticos (mecanorreceptores - metaborreceptores) es una hipótesis propuesta recientemente para explicar el origen de los síntomas de fatiga y disnea y de los efectos benéficos del entrenamiento físico en el síndrome de IC. En la IC, otras alteraciones en los sistemas de control reflejo, que no son mutuamente exclusivos, contribuyen a la disnea. Estimulación inapropiada de los barorreceptores arteriales, con consecuente falta de inhibición de la descarga del metaborreflejo muscular y quimiorreflejo carotídeo, y el aumento de la vasoconstricción renal con liberación de angiotensina II se pueden también tener en cuenta. A pesar de las alteraciones funcionales de los reflejos haber sido utilizadas de manera independiente para ilustrar la excitación simpática observada en la IC, la interacción entre estos reflejos en condiciones normales y patológicas, especialmente su contribución para el estado simpatoexcitatorio encontrado en la IC, no viene siendo ampliamente estudiada. De este modo, resta todavía un cuestionamiento sobre la posible relación entre los receptores musculares (mecano y metaborreceptores) en la génesis de la exacerbación del ergorreflejo observado en la IC. Por tanto, esta revisión tiene por objetivo integrar los conocimientos respecto al mecano y metaborreflejo (ergorreflejo) en el síndrome de la insuficiencia cardiaca, así como aclarar la influencia de la terapéutica medicamentosa de la IC en el ergorreflejo.