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.

An improved strategy for evaluating the extent of chronic arterial baroreceptor denervation in conscious rats

There is no index or criterion of aortic barodenervation, nor can we differentiate among rats that have suffered chronic sham, aortic or sino-aortic denervation. The objective of this study was to develop a procedure to generate at least one quantitative, reproducible and validated index that precisely evaluates the extent of chronic arterial barodenervation performed in conscious rats. Data from 79 conscious male Wistar rats of about 65-70 days of age with diverse extents of chronic arterial barodenervation and used in previous experiments were reanalyzed. The mean arterial pressure (MAP) and the heart rate (HR) of all rats were measured systematically before (over 1 h) and after three consecutive iv bolus injections of phenylephrine (PHE) and sodium nitroprusside (SNP). Four expressions of the effectiveness of barodenervation (MAP lability, PHE ratio, SNP ratio, and SNP-PHE slope) were assessed with linear fixed models, three-level average variance, average separation among levels, outlier box plot analysis, and overlapping graphic analysis. The analysis indicated that a) neither MAP lability nor SNP-PHE slope was affected by the level of chronic sodium intake; b) even though the Box-Cox transformations of both MAP lability [transformed lability index (TLI)] and SNP-PHE slope [transformed general sensitivity index (TGSI), {((3-(ΔHRSNP-ΔHRPHE/ΔMAPSNP-ΔMAPPHE))-0.4-1)/-0.04597}] could be two promising indexes, TGSI proved to be the best index; c) TLI and TGSI were not freely interchangeable indexes for this purpose. TGSI ranges that permit differentiation between sham (10.09 to 11.46), aortic (8.40 to 9.94) and sino-aortic (7.68 to 8.24) barodenervated conscious rats were defined.

Cardiovascular sensory receptors and their regulatory mechanisms.

The role of cardiovascular receptors in the neural regulation of circulatory system is now well established. Atrial type B receptors located in the two atria and veno-atrial junctions, which are stimulated by atrial filling are believed to play an important role in the regulation of body fluid volume and heart rate. Heart rate is influenced also by other sensory receptors e.g. arterial baroreceptors, ventricular receptors, pulmonary stretch receptors and chemoreceptors. Of all these visceral receptors, arterial baroreceptors located mainly in the aortic arch and the carotid sinus region are stimulated by intravascular pressure; play a major role in the regulation of blood pressure by changes in heart rate and vascular tone. The vascular tone is also affected by the circulatory levels of various neurotransmitters and hormones. Vasodilatory response to adenosine and acetylcholine is partly mediated through endothelium-derived relaxing factors (EDRF), hyperpolarizing factors (EDHF) and contracting factors (EDCF). The endothelium-dependent mechanisms are altered during hypertension and diabetes. The autonomic control of blood pressure is primarily through arterial baroreceptors. The sensitivity of the baroreceptor heart rate reflex is significantly attenuated on occlusion of left anterior descending coronary artery (LAD) of anaesthetised dogs taken as an experimental model of coronary insufficiency in-patients of coronary heart disease. The fall in the sensitivity of baroreflex on LAD occlusion is mediated primarily by sympathetic limb of the autonomic nervous system. Acute fall in hemoglobin level by hemodilution in dogs produced an increase in cardiac output by increasing the heart rate through inhibition of parasympathetic tone. After parasympathetic blockade the increase in cardiac output on fall in hemoglobin was due to a rise in the stroke volume. Acute fall in hemoglobin level attenuated the baroreflex response. Sustained changes in blood pressure cause resetting of baroreflex i.e. increase in arterial pressure involves reduced activity of baroreceptors at equivalent pressure and vascular stretch. Like in acute hypoxia the altered responsiveness of baroreceptor heart rate reflex during oxygen deficiency due to acute occlusion of LAD or acute normovolemic hemodilution may involve both peripheral and central components and possibility of modulation by circulating hormones also exists.

Pharmacological studies on sesame and nigella sativa fixed oils: effects on the sensitivities of the adrenoceptors baroreceptors, platelets and the uterus of the rat

The aim of this study is to unravel the effects of short-term treatment [2 weeks] with sesame oil [S.O., 6 and 12 ml Kg[-1]. Day [-1], i.p.] and Nigella sativa fixed oil [N.O. 2 and 2 ml Kg[-1] Day[-1] i.p.] on some cardiovascular, platelets and reproductive parameters in normal and/or streptozotocin hyperglycemic diabetic rats [NR and DR, respectively]. Both S.O. and N.O. significantly suppressed [alpha] -adrenoceptor-mediated phenylephrine-induced rise in the arterial blood pressure in NR only. S.O. significantly sensitized the arterial baroreceptors, whereas N.O. significantly suppressed it in NR only. None of the oils affected this parameter in the DR. Both oils significantly enhanced isoprenaline-induced hypotension in both NR and DR without any effect on isoprenaline-induced tachycardia. Both oils suppressed adenosine diphosphate [ADP]-induced platelets aggregation in both NR and DR. The suppression was more significant in DR. Both oils enhanced significantly arachidonic acid [0.714 mg Kg[1] i.v.] -induced hypotension in NR. Both oils significantly suppressed PGE[2-] and oxytocin-induced uterine contractions of the diethylstilbesterol-treated uteri of the NR. S.O. but not N.O. significantly enhanced the percentage of bias to cysts implantation in NR. None of the oils induced any teratogenic effects or induced significant changes in the gestation length, litter size, male to female ratio, resorption rate or placental weights in NR. However, N.O. significantly increased the foetal weight. In conclusion, the results point to the potential usefulness of both S.O. and N.O. in conditions that benefit from desensitization of [alpha1] adrenoceptors, [Beta2] sensitization of -adrenoceptors and uterine PGE[2] and oxytocin receptors. Furthermore, S.O.-induced sensitization of the baroreceptors may be beneficial in those conditions associated with a decrease in arterial baroretlexes. In addition, both oils seemed to be safe during pregnancy with S.O. having the additional potential advantage of enhancing the implantation rate

Functional evidence that the central renin-angiotensin system plays a role in the pressor response induced by central injection of cabachol

We investigated the effects of losartan, an AT1-receptor blocker, and ramipril, a converting enzyme inhibitor, on the pressor response induced by angiotensin II (ANG II) and carbachol (a cholinergic receptor agonist). Male Holtzman rats (250-300 g) with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The injection of losartan (50 nmol/l mul) into the LV blocked the pressor response induced by ANG II (12 ng/1 mul) and carbachol (2 nmol/ 1 mul). After injection of ANG II and carbachol into the LV, mean arterial pressure (MAP) increased to 31 + 1 and 28 + 2 mmHg, respectively. Previous injection of losartan abolished the increase in MAP induced by ANG II and carbachol into the LV (2 + 1 and 5 + 2 mmHg, respectively). The injection of ramipril (12 ng/ 1 mul) prior to carbachol blocked the pressor effect of carbachol to 7 + 3 mmHg. These results suggests an interaction between central cholinergic pathways and the angiotensinergic system in the regulation of arterial blood pressure.

Neural reflex regulation of arterial pressure in pathophysiological conditions: interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex

The maintenance of arterial pressure at levels adequate to perfuse the tissues is a basic requirement for the constancy of the internal environment and survival.The objective of the present review was to provide information about the basic relfex mechanisms that are responsible for the moment-to-moment regulation of the cardiovascular system. We demonstrate that this control is largely provided by the action of arterial and non-arterial reflexes that detect and correct changes in arterial pressure (baroreflex), blood volume or chemical composition (mechano-and chemosensitive cardiopulmonary reflexes), and changes in bloodgas composition (chemoreceptor reflex). The importance of the integration of these cardiovascular reflexes is well understood and it is clear that processing mainly occurs in the nucleus tractus solitarii, although the mechanism is poorly understood.There are several indications that the interactions of baroreflex, chemoreflex and Bezold-Jarisch reflex inputs, and the central nervous system control the activity of autonomic preganglionic neurons through parallel afferent and efferent pathways to achieve cardiovascular homeostasis. It is surprising that so little appears in the literature about the integration of these neural reflexes in cardiovascular function. Thus, our purpose was to review the interplay between peripheral neural reflex mechanisms of arterial blood pressure and blood volume regulation in physiological and pathophysiological states. Special emphasis is placed on the experimental model or arterial hypertension induced by N-nitro-L-arginine methyl ester (L-NAME) in which the interplay of these three reflexes is demonstrable.

Autonomic processing of the cardiovascular reflexes in the nucleus tractus solitarii

The nucleus tractus solitarii (NTS) receives afferent projections from the arterial baroreceptors, carotid chemoreceptors and cardiopulmonary receptors and as a function of this information produces autonomic adjustments in order to maintain arterial blood pressure within a narrow range of variation.The activation of each of these cardiovascular afferents produces a specific autonomic response by the excitation of neuronal projections from the NTS to the ventrolateral areas of the medulla (nucleus ambiguus, caudal and rostral ventrolateral medulla). The neurotransmitters at the NTS level as well as the excitatory amino acid (EAA) receptors involved in the processing of the autonomic responses in the NTS, although extensively studied, remain to be completely elucidated. In the present review we discuss the role of the EAA L-glutamate and its different receptor subtypes in the processing of the cardiovascular reflexes in the NTS. The data presented in this review related to the neurotransmission in the NTS are based on experimental evidence obtained in our laboratory in unanesthetized rats. The two major conclusions of the present review are that a) the excitation of the cardiovagal component by cardiovascular relfex activation (chemo- and Bezold-Jarisch reflexes) or by L-glutamatae microinjection into the NTS is mediated by N-methyl-D-aspartate (NMDA) receptors, and b) the sympatho-excitatory componente of the chemoreflex and the pressor response to L-glutamate microinjected into the NTS are not affected by an NMDA receptor antagonist, suggesting that the sympatho-excitatory component of these responses is mediated by non-NMDA receptors.

Effect of melatonin on baroreflex control of heart rate in rabbits

The effect of intravenous injection of melatonin [0.1 mg/kg, 0.5 mg/Kg and 1 mg/Kg] on arterial blood pressure and heart rate in adult male rabbits was investigated in this study. Baroreflex function was assessed using phenylephrine [the pressor test] to induce moderate changes in arterial blood pressure and to alter the stimulation of baroreceptor sites. In addition, the effect of melatonin on sympathetic and parasympathetic efferent nerve activity was also investigated. Melatonin resulted in a lowering effect on arterial blood -pressure with a decrease in heart rate. The significant decrease of arterial blood pressure was observed at a dose as low as 0.5 mg/Kg. The lowering effect of melatonin on heart rate was detected at 1 mg/Kg. Baroreflex slope was not depressed significantly with a significant increase in pulse interval, until I mg/Kg melatonin. Sympathetic and vagal nerve activities were attenuated significantly by melatonin. This study indicated that baroreflex control of heart rate was depressed by intravenous administration of melatonin. There was a dissociation between the effect of melatonin on baroreflex sensitivity versus the effect of low blood pressure. Melatonin was found to alter the baroreflex heart rate response through its direct depressant effect on baroreceptors and on both sympathetic and parasympathetic efferent nerve pathways

Alteraçäo do nível operacional dos barorreceptores sob a açäo do verapamil na hipertensäo arterial / Operational alteration of baroreceptors following verapamil in arterial hypertension

O objetivo do trabalho é explicar por que o verapamil, quando usado sob a forma de infusäo venosa seqüencial, por alguns dias, é capaz de tornar o paciente, antes resistente, novamente sensível aos medicamentos anti-hipertensivos convencionais. O método empregado foi o teste de avaliaçäo funcional dos barorreceptores com a fenilefrina, antes e depois da série de infusöes. O estudo foi feito em dez pacientes portadores de hipertensäo resistentes ao tratamento convencional. O teste mostrou em todos os casos, uma resposta vagal linearmente dependente da elevaçäo da pressäo sistólica. Todoso os pacientes, após a série de infusöes venosas de verapamil, apresentavam no teste, uma resposta da pressäo que se iniciava em nível muito mais baixo, indicando que o arco reflexo estava, neste momento, reajustado em níveis mais inferiores; também, depois das infusöes seriadas com o verapamil, o teste mostrou uma bradicardia reflexa e uma maior inclinaçäo da linha de regressäo, indicando nesta situaçäo terapêutica, uma maior sensibilidade dos barorreceptores. A infusäo seqüencial diária do verapamil altera os níveis operacionais dos barorreceptores, reajustando inferiormente o nível da resposta pressórica e aumentando a sensibilidade dos mesmos