Chronic administration of catalase inhibitor attenuates hypertension in renovascular hypertensive rats.

AIMS: Reactive oxygen species like hydrogen peroxide (H2O2) are produced endogenously and may participate in intra- and extracellular signaling, including modulation of angiotensin II responses. In the present study, we investigated the effects of chronic subcutaneous (sc) administration of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ) on arterial pressure, autonomic modulation of arterial pressure, hypothalamic expression of AT1 receptors and neuroinflammatory markers and fluid balance in 2-kidney, 1clip (2K1C) renovascular hypertensive rats. MATERIALS AND METHODS: Male Holtzman rats with a clip occluding partially the left renal artery and chronic sc injections of ATZ were used. KEY FINDINGS: Subcutaneous injections of ATZ (600 mg/kg of body weight/day) for 9 days in 2K1C rats reduced arterial pressure (137 ± 8, vs. saline: 182 ± 8 mmHg). ATZ also reduced the sympathetic modulation and enhanced the parasympathetic modulation of pulse interval, reducing the sympatho-vagal balance. Additionally, ATZ reduced mRNA expression for interleukins 6 and IL-1ß, tumor necrosis factor-α, AT1 receptor (0.77 ± 0.06, vs. saline: 1.47 ± 0.26 fold change), NOX 2 (0.85 ± 0.13, vs. saline: 1.75 ± 0.15 fold change) and the marker of microglial activation, CD 11 (0.47 ± 0.07, vs. saline, 1.34 ± 0.15 fold change) in the hypothalamus of 2K1C rats. Daily water and food intake and renal excretion were only slightly modified by ATZ. SIGNIFICANCE: The results suggest that the increase of endogenous H2O2 availability with chronic treatment with ATZ had an anti-hypertensive effect in 2K1C hypertensive rats. This effect depends on decreased activity of sympathetic pressor mechanisms and mRNA expression of AT1 receptors and neuroinflammatory markers possibly due to reduced angiotensin II action.

The carotid body detects circulating tumor necrosis factor-alpha to activate a sympathetic anti-inflammatory reflex.

Recent evidence has suggested that the carotid bodies might act as immunological sensors, detecting pro-inflammatory mediators and signalling to the central nervous system, which, in turn, orchestrates autonomic responses. Here, we confirmed that the TNF-α receptor type I is expressed in the carotid bodies of rats. The systemic administration of TNF-α increased carotid body afferent discharge and activated glutamatergic neurons in the nucleus tractus solitarius (NTS) that project to the rostral ventrolateral medulla (RVLM), where many pre-sympathetic neurons reside. The activation of these neurons was accompanied by an increase in splanchnic sympathetic nerve activity. Carotid body ablation blunted the TNF-α-induced activation of RVLM-projecting NTS neurons and the increase in splanchnic sympathetic nerve activity. Finally, plasma and spleen levels of cytokines after TNF-α administration were higher in rats subjected to either carotid body ablation or splanchnic sympathetic denervation. Collectively, our findings indicate that the carotid body detects circulating TNF-α to activate a counteracting sympathetic anti-inflammatory mechanism.

Mesenchymal stromal cells-based therapy in a murine model of elastase-induced emphysema: Simvastatin as a potential adjuvant in cellular homing.

Chronic Obstructive Pulmonary Disease - COPD is characterized by the destruction of alveolar walls associated to a chronic inflammatory response of the airways. There is no clinical therapy for COPD. In this context, cell-based therapies represent a promising therapeutic approach for chronic lung disease. The goal of this work was to evaluate the effect of simvastatin on cell-based therapy in a mice emphysema model. Female FVB mice received intranasal instillation of elastase (three consecutive doses of 50 µL) in order to promote pulmonary emphysema. After 21 days of the first instillation, the animals were treated with Adipose-Derived Mesenchymal Stromal Cells (AD-MSC, 2.6 × 106) via retro-orbital infusion associated or not with simvastatin administrated daily via oral gavage (15 mg/kg/15d). Before and after these treatments, the histological and morphometrical analyses of the lung tissue, as so as lung function (whole body plethysmography) were evaluated. PAI-1 gene expression, an upregulated factor by ischemia that indicate a low survival of transplanted MSC, was also evaluated. The result regarding morphological and functional aspects of both lungs, presented no significant difference among the groups (AD-MSC or AD-MSC + Simvastatin). However, significant anatomical difference was observed in the right lung of the both groups of mice. The results shown a higher deposition of cells in the right lung, with might to be explained by anatomical differences (slightly higher right bronchi). Decreased levels of PAI-1 were observed in the simvastatin treated groups. The pulmonary ventilation was similar between the groups with only a tendency to a lower in the elastase treated animals due to a low respiratory frequency. In conclusion, the results suggest that both AD-MSC and simvastatin treatments could promote an improvement of morphological recovery of pulmonary emphysema, that it was more pronounced in the right lung.

ANG II and Aldosterone Acting Centrally Participate in the Enhanced Sodium Intake in Water-Deprived Renovascular Hypertensive Rats.

Renovascular hypertension is a type of secondary hypertension caused by renal artery stenosis, leading to an increase in the renin-angiotensin-aldosterone system (RAAS). Two-kidney, 1-clip (2K1C) is a model of renovascular hypertension in which rats have an increased sodium intake induced by water deprivation (WD), a common situation found in the nature. In addition, a high-sodium diet in 2K1C rats induces glomerular lesion. Therefore, the purpose of this study was to investigate whether angiotensin II (ANG II) and/or aldosterone participates in the increased sodium intake in 2K1C rats under WD. In addition, we also verified if central AT1 and mineralocorticoid receptor blockade would change the high levels of arterial pressure in water-replete (WR) and WD 2K1C rats, because blood pressure changes can facilitate or inhibit water and sodium intake. Finally, possible central areas activated during WD or WD followed by partial rehydration (PR) in 2K1C rats were also investigated. Male Holtzman rats (150-180 g) received a silver clip around the left renal artery to induce renovascular hypertension. Six weeks after renal surgery, a stainless-steel cannula was implanted in the lateral ventricle, followed by 5-7 days of recovery before starting tests. Losartan (AT1 receptor antagonist) injected intracerebroventricularly attenuated water intake during the thirst test. Either icv losartan or RU28318 (mineralocorticoid receptor antagonist) reduced 0.3 M NaCl intake, whereas the combination of losartan and RU28318 icv totally blocked 0.3 M NaCl intake induced by WD in 2K1C rats. Losartan and RU28318 icv did not change hypertension levels of normohydrated 2K1C rats, but reduced the increase in mean arterial pressure (MAP) produced by WD. c-Fos expression increased in the lamina terminalis and in the NTS in WD condition, and increased even more after WD-PR. These results suggest the participation of ANG II and aldosterone acting centrally in the enhanced sodium intake in WD 2K1C rats, and not in the maintenance of hypertension in satiated and fluid-replete 2K1C rats.

Electrocardiographic changes in the acute hyperkalaemia produced by intragastric KCl load in rats.

NEW FINDINGS: What is the central question of this study? This study presents a new model for studying the rapid onset of severe, acute hyperkalaemia in rats with intact kidney function by administering an intragastric KCl load. What is the main finding and its importance? This new model of intragastric KCl load produces a reliable and reproducible model for studying the rapid onset of severe, acute hyperkalaemia in rats with intact kidney function. We report unprecedented rapid changes (30 min) in ECG, blood pressure and various arterial blood analyses with this new model, providing a solid foundation for future experiments in this field. ABSTRACT: A variety of animal models have been proposed to study hyperkalaemia, but most of them have meaningful limitations when the goal is to study the effect of potassium overload on healthy kidneys. In this study, we aimed to introduce a new approach for induction of hyperkalaemia in a reliable and reproducible animal model. We used intragastric administration of potassium chloride [KCl 2.3 M, 10 ml/(kg body weight)] to male Holtzman rats (300-350 g) to induce hyperkalaemia. The results showed that this potassium load can temporarily overwhelm the renal and extrarenal handling of this ion, causing an acute and severe hyperkalaemia that can be useful to study the effect of potassium imbalance in a variety of scenarios. Severe hyperkalaemia (>8 meqiv/l) and very profound ECG alterations, characterized by lengthening waves and intervals, were seen as early as 30 min after intragastric administration of KCl in rats. In addition, a transient increase in arterial blood pressure and time-dependent bradycardia were also seen after the KCl administration. No metabolic acidosis was present in the animals, and the potassium ion did not increase proportionally to chloride ion in the blood, leading to an increased anion gap. In conclusion, the results suggest that intragastric KCl loading is a reliable model to promote rapid and severe hyperkalaemia that can be used for further research on this topic.

Importance of the commissural nucleus of the solitary tract in renovascular hypertension.

The rodent renovascular hypertension model has been used to investigate the mechanisms promoting hypertension. The importance of the carotid body for renovascular hypertension has been demonstrated. As the commissural NTS (cNTS) is the first synaptic site in the central nervous system that receives information from carotid body chemoreceptors, we evaluated the contribution of cNTS to renovascular hypertension in the present study. Normotensive male Holtzman rats were implanted with a silver clip around the left renal artery to induce two-kidney, one-clip (2K1C) hypertension. Six weeks later, isoguvacine (a GABAA agonist) or losartan (an AT1 antagonist) was injected into the cNTS, and the effects were compared with carotid body removal. Immunohistochemistry for Iba-1 and GFAP to label microglia and astrocytes, respectively, and RT-PCR for components of the renin-angiotensin system and cytokines in the NTS were also performed 6 weeks after renal surgery. The inhibition of cNTS with isoguvacine or the blockade of AT1 receptors with losartan in the cNTS decreased the blood pressure and heart rate of 2K1C rats even more than carotid body removal did. The mRNA expression of NOX2, TNF-α and IL-6, microglia, and astrocytes also increased in the cNTS of 2K1C rats compared to that of normotensive rats. These results indicate that tonically active neurons within the cNTS are essential for the maintenance of hypertension in 2K1C rats. In addition to signals from the carotid body, the present results suggest that angiotensin II directly activates the cNTS and may also induce microgliosis and astrogliosis within the NTS, which, in turn, cause oxidative stress and neuroinflammation.

Role of the Carotid Bodies in the Hypertensive and Natriuretic Responses to NaCl Load in Conscious Rats.

Hyperosmotic challenges trigger a hypertensive response and natriuresis mediated by central and peripheral sensors. Here, we evaluated the importance of the carotid bodies for the hypertensive and natriuretic responses to acute and sub-chronic NaCl load in conscious rats. Male Wistar rats (250-330 g) submitted to bilateral carotid body removal (CBX) or sham surgery were used. One day after the surgery, the changes in arterial blood pressure (n = 6-7/group) and renal sodium excretion (n = 10/group) to intravenous infusion of 3 M NaCl (1.8 mL/kg b.w. during 1 min) were evaluated in non-anesthetized rats. Another cohort of sham (n = 8) and CBX rats (n = 6) had access to 0.3 M NaCl as the only source of fluid to drink for 7 days while ingestion and renal excretion were monitored daily. The sodium balance was calculated as the difference between sodium infused/ingested and excreted. CBX reduced the hypertensive (8 ± 2 mmHg, vs. sham rats: 19 ± 2 mmHg; p < 0.05) and natriuretic responses (1.33 ± 0.13 mmol/90 min, vs. sham: 1.81 ± 0.11 mmol/90 min; p < 0.05) to acute intravenous infusion of 3 M NaCl, leading to an increase of sodium balance (0.38 ± 0.11 mmol/90 min, vs. sham: -0.06 ± 0.10 mmol/90 min; p < 0.05). In CBX rats, sub-chronic NaCl load with 0.3 M NaCl to drink for 7 days increased sodium balance (18.13 ± 4.45 mmol, vs. sham: 5.58 ± 1.71 mmol; p < 0.05) and plasma sodium concentration (164 ± 5 mmol/L, vs. sham: 140 ± 7 mmol/L; p < 0.05), without changing arterial pressure (121 ± 9 mmHg, vs. sham: 116 ± 2 mmHg). These results suggest that carotid bodies are important for the maintenance of the hypertensive response to acute hypertonic challenges and for sodium excretion to both acute and chronic NaCl load.

Enhanced angiotensin II induced sodium appetite in renovascular hypertensive rats.

Renovascular hypertensive 2-kidney, 1-clip (2K1C) rats have an increased activity of the renin-angiotensin system and an initial transitory increase in daily water and NaCl intake. However, the dipsogenic and natriorexigenic responses to angiotensin II (ANG II) have not been tested yet in 2K1C rats. Therefore, in the present study, we evaluated water and 0.3 M NaCl intake induced by water deprivation (WD)-partial rehydration (PR) or intracerebroventricular (icv) ANG II in 2K1C rats. In addition, the cardiovascular changes to these treatments were also evaluated. Male Holtzman rats received a silver clip around the left renal artery to induce 2K1C renovascular hypertension. In the 5th week, a group of animals received a guide cannula in the lateral ventricle for icv injections. Daily water intake increased from the 3rd week after surgery and remained elevated until the 6th week (last recording week), whereas daily 0.3 M NaCl intake transiently increased from the 2nd to the 5th week after surgery. On the 6th week, in spite of comparable daily 0.3 M NaCl intake between 2K1C and sham rats, WD-PR and icv ANG II induced an increased 0.3 M NaCl intake in 2K1C rats. Water intake induced by WD-PR, not by icv ANG II, also increased in 2K1C rats. The increase in arterial pressure to WD-PR or icv ANG II was similar in sham and 2K1C rats. Therefore, these results suggest that 2K1C rats are more responsive to the natriorexigenic effects of ANG II, whereas other responses to ANG II are not modified.

Overexpression of AT2R in the solitary-vagal complex improves baroreflex in the spontaneously hypertensive rat.

The aim of this study was to investigate the physiological effects of increased angiotensin II type 2 receptor (AT2R) expression in the solitary-vagal complex (nucleus of the solitary tract/dorsal motor nucleus of the vagus; NTS/DVM) on baroreflex function in non-anaesthetised normotensive (NT) and spontaneously hypertensive rats (SHR). Ten week old NT Holtzman and SHR were microinjected with either an adeno-associated virus expressing AT2R (AAV2-CBA-AT2R) or enhanced green fluorescent protein (control; AAV2-CBA-eGFP) into the NTS/DVM. Baroreflex and telemetry recordings were performed on four experimental groups: 1) NTeGFP, 2) NTAT2R, 3) SHReGFP and 4) SHRAT2R (n=4-7/group). Following in-vivo experimental procedures, brains were harvested for gene expression analysis. Impaired bradycardia in SHReGFP was restored in SHR rats overexpressing AT2R in the NTS/DMV. mRNA levels of angiotensin converting enzyme decreased and angiotensin converting enzyme 2 increased in the NTS/DMV of SHRAT2R compared to SHReGFP. Increased levels of pro-inflammatory cytokine mRNA levels in the SHReGFP group also decreased in the SHRAT2R group. AT2R overexpression did not elicit any significant change in mean arterial pressure (MAP) in all groups from baseline to 4weeks post viral transfection. Both SHReGFP and SHRAT2R showed a significant elevation in MAP compared to the NTeGFP and NTAT2R groups. Increased AT2R expression within the NTS/DMV of SHR was effective at improving baroreflex function but not MAP. We propose possible mediators involved in improving baroreflex are in the ANG II/ACE2 axis, suggesting a potential beneficial modulatory effect of AT2R overexpression in the NTS/DMV of neurogenic hypertensive rats.

Resistance training prevents the cardiovascular changes caused by high-fat diet.

AIMS: Aerobic exercise is indicated for prevention and treatment of obesity-induced cardiovascular disorders. Although the resistance training (RT) may also produce effects similar to aerobic exercise, this is not completely clear yet. In the present study, we tested if RT in moderate intensity might prevent alterations in blood pressure (BP), sympathetic modulation of systolic blood pressure (SBP), baroreflex function and the changes in renin-angiotensin system (RAS) and cytokines mRNA expression within the nucleus of the tract solitary (NTS) in rats fed with high-fat diet (HFD). MAIN METHODS: Male Holtzman rats (300-320 g) were divided into 4 groups: sedentary with standard chow diet (SED-SD); sedentary with high-fat diet (SED-HFD); RT with standard chow diet (RT-SD); and RT with high-fat diet (RT-HFD). The trained groups performed a total of 10 weeks of moderate intensity RT in a vertical ladder. In the first 3 weeks all experimental groups were fed with SD. In the next 7 weeks, the SED-HFD and RT-HFD groups were fed with HFD. KEY FINDINGS: In SED-HFD, BP and sympathetic modulation of SBP increased, whereas baroreflex bradycardic responses were attenuated. RT prevented the cardiovascular and inflammatory responses (increases in tumoral necrosis factor-α and interleukin-1ß) produced by HFD in SED rats. The anti-inflammatory interleukin-10, angiotensin type 2 receptor, Mas receptor and angiotensin converting enzyme 2 mRNA expressions in the NTS increased in the RT-HFD compared to SED-HFD. SIGNIFICANCE: The data demonstrated that moderate intensity RT prevented obesity-induced cardiovascular disorders simultaneously with reduced inflammatory responses and modifications of RAS in the NTS.

Increased expression of angiotensin II type 2 receptors in the solitary-vagal complex blunts renovascular hypertension.

Angiotensin II increases and decreases arterial pressure by acting at angiotensin type 1 and type 2 receptors, respectively. Renovascular hypertensive rats exhibit a high level of activity of the peripheral and central renin-angiotensin system. Therefore, in the present study, we evaluated the effect of increasing the expression of angiotensin type 2 receptors in the solitary-vagal complex (nucleus of the solitary tract/dorsal motor nucleus of the vagus), a key brain stem region for cardiovascular regulation, on the development of renovascular hypertension. Holtzman normotensive rats were implanted with a silver clip around the left renal artery to induce 2-kidney 1-clip renovascular hypertension. Three weeks later, rats were microinjected in the solitary-vagal complex with either an adenoassociated virus to increase the expression of angiotensin type 2 receptors or with a control vector. We observed that increasing angiotensin type 2 receptor expression in the solitary-vagal complex attenuated the development of renovascular hypertension and also reversed the impairment of the baroreflex and the increase in the low-frequency component of systolic blood pressure observed in renovascular hypertensive rats. Furthermore, an observed decrease in mRNA levels of angiotensin-converting enzyme 2 in the solitary-vagal complex of renovascular hypertensive rats was restored to control levels after viral-mediated increases in angiotensin type 2 receptors at this site. Collectively, these data demonstrate specific and beneficial effects of angiotensin type 2 receptors via the brain of hypertensive rats and suggest that central angiotensin type 2 receptors may be a potential target for therapeutics in renovascular hypertension.

Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality.

The nucleus of the solitary tract (NTS) is the primary site of visceral afferents to the central nervous system. In the present study, we investigated the effects of lesions in the commissural portion of the NTS (commNTS) on the activity of vasopressinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, plasma vasopressin, arterial pressure, water intake, and sodium excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats with 15-20 days of sham or electrolytic lesion (1 mA; 10 s) of the commNTS were used. CommNTS lesions enhanced a 2 M NaCl intragastrically induced increase in the number of vasopressinergic neurons expressing c-Fos in the PVN (28 ± 1, vs. sham: 22 ± 2 c-Fos/AVP cells) and SON (26 ± 4, vs. sham: 11 ± 1 c-Fos/AVP cells), plasma vasopressin levels (21 ± 8, vs. sham: 6.6 ± 1.3 pg/ml), pressor responses (25 ± 7 mmHg, vs. sham: 7 ± 2 mmHg), water intake (17.5 ± 0.8, vs. sham: 11.2 ± 1.8 ml/2 h), and natriuresis (4.9 ± 0.8, vs. sham: 1.4 ± 0.3 meq/1 h). The pretreatment with vasopressin antagonist abolished the pressor response to intragastric 2 M NaCl in commNTS-lesioned rats (8 ± 2.4 mmHg at 10 min), suggesting that this response is dependent on vasopressin secretion. The results suggest that inhibitory mechanisms dependent on commNTS act to limit or counterbalance behavioral, hormonal, cardiovascular, and renal responses to an acute increase in plasma osmolality.

Macrophage migration inhibitory factor in the nucleus of solitary tract decreases blood pressure in SHRs.

AIMS: The macrophage migration inhibitory factor (MIF) is an intracellular inhibitor of the central nervous system actions of angiotensin II on blood pressure. Considering that angiotensin II actions at the nucleus of the solitary tract are important for the maintenance of hypertension in spontaneously hypertensive rats (SHRs), we tested if increased MIF expression in the nucleus of the solitary tract of SHR alters the baseline high blood pressure in these rats. METHODS AND RESULTS: Eight-week-old SHRs or normotensive rats were microinjected with the vector AAV2-CBA-MIF into the nucleus of the solitary tract, resulting in MIF expression predominantly in neurons. Rats also underwent recordings of the mean arterial blood pressure (MAP) and heart rate (via telemetry devices implanted in the abdominal aorta), cardiac- and baroreflex function. Injections of AAV2-CBA-MIF into the nucleus of the solitary tract of SHRs produced significant decreases in the MAP, ranging from 10 to 20 mmHg, compared with age-matched SHRs that had received identical microinjections of the control vector AAV2-CBA-eGFP. This lowered MAP in SHRs was maintained through the end of the experiment at 31 days, and was associated with an improvement in baroreflex function to values observed in normotensive rats. In contrast to SHRs, similar increased MIF expression in the nucleus of the solitary tract of normotensive rats produced no changes in baseline MAP and baroreflex function. CONCLUSION: These results indicate that an increased expression of MIF within the nucleus of the solitary tract neurons of SHRs lowers blood pressure and restores baroreflex function.

Bovine pericardium retail preserved in glutaraldehyde and used as a vascular patch.

BACKGROUND: In this study we evaluated the performance of bovine pericardium preserved in glutaraldehyde used as a vascular patch. METHODS: Fourteen young pigs, six females and eight males, weighting 10.3 - 18.4 kg were used in our study. We implanted three remnants in each pig, two in the abdominal aorta and one was juxtaposed to the peritoneum. The smooth face (SF) and rough face (RF) of each remnant were implanted turned to the vessel inner portion and one remnant was juxtaposed to the peritoneum. The animals were sacrificed in 4.5 - 8 months after surgery (75 - 109 kg). The remnants were assessed for aorta wall, fibroses formation in inner apposition and calcification related to the face turned to the vessel inner portion. RESULTS: The rough face showed a lower dilatation level compared to the face implanted in adjacent aorta. There was no difference between intensity and/or incidence of graft calcification when the superficies were compared. The bovine pericardium preserved in glutaraldehyde did not show alterations in its structure when implanted with different faces turned to the inner portion of vessel. CONCLUSION: When turned to the inner portion of the vessel, the rough face of the remnant presented a lower dilatation in relation to the adjacent aorta and a better quality of endothelium layer and did not show a difference between intensity and/or incidence of graft calcification.

Mecanismos neuro-hormonais envolvidos na regulação do apetite ao sódio: alguns aspectos / Neuro-hormonal mechanisms involved within sodium appetite: some aspects

O sódio é o principal íon do líquido extracelular e tem primordial importância para diversas funções fisiológicas. Manter a concentração plasmática do sódio dentro dos limites fisiológicos é vital para diversas espécies de animais, inclusive os humanos. Portanto, é fundamental que hajam mecanismos responsáveis pela monitorização e manutenção de níveis adequados de sódio no plasma. O apetite ao sódio, o comportamento que comanda a ingestão de sal, é estimulado por situações de deficiência sistêmica de sódio. Ao longo de décadas, diversos estudos foram desenvolvidos a fim de compreender os mecanismos neurais e hormonais envolvidos no controle desse comportamento. No entanto, muitas questões relacionadas a esse assunto ainda permanecem desconhecidas e a cada dia surgem novas evidências. Neste trabalho, foram revistos os fatos históricos, mecanismos neurais, hormonais e os achados mais recentes envolvendo apetite ao sódio.

Sodium is the most important ion of the extracellular fluid and plays an important role for many physiological functions. Maintain the sodium concentration in the plasma around of its physiological values is vital for many species of animals, including humans. Therefore, it is important that have responsible mechanisms for monitorization and maintenance of appropriated levels of plasmatic sodium. Sodium appetite, the behavioral drive to ingest salt, is stimulated by systemic sodium deficiency. Over the past decades, several studies have been performed in order to understand the neural and hormonal mechanisms involved in the control of this behavior. However, many questions related to this issue are still unknown and everyday new evidences arise. Here, we review historical facts, neural and hormonal mechanisms and recent findings involving sodium appetite.

Importância do sistema nervoso no controle da micção e armazenamento urinário: [revisão] / The importance of the nervous system in the control of voiding and urine storage: [review]

O controle da micção, apesar da aparente simplicidade em seu funcionamento, apresenta vários níveis de regulação com relativa complexidade. Em estados conscientes e inconscientes, envolve a atividade de nervos periféricos, da medula sacral e das áreas centrais que constituem o bulbo, a ponte, o mesencéfalo e o córtex. Neste trabalho de revisão serão abordados quais são as áreas centrais atualmente conhecidas por participarem do controle da micção e armazenamento urinário, assim como a sinalização proveniente do sistema nervoso periférico, que se dirige ao trato urinário inferior. Realizouse uma busca nas bases de dados Pubmed e Scielo utilizando descritores para obter informações sobre o controle central da micção e o armazenamentourinário. A primeira porção do tronco encefálico que demonstrou relação com atividade miccional foi a ponte, principalmente o centro miccional pontino (PMC). É um ponto de convergência de estímulos pró e antimicção e sua principal função é ser o centro de comando para o início e harmonia do esvaziamento vesical. Diferentes regiões distintas disparam após a micção, sugerindo existir neurônios sinalizadores do início do relaxamento detrusor. A substância cinzenta periaquedutal é uma área importante no controle central do trato urinário inferior. Recebe modulação inibitória da região posterior hipotalâmica, envolvida no mecanismo de defesa (luta ou fuga). Outras estruturas como córtex, núcleos da base e cerebelo também vêm sendo evidenciadas por modular a micção. Embora neurônios bulbares sejam conhecidos por integrarem diferentes tipos de informações somatoviscerais e, principalmente, por participarem na regulação cardiovascular, pouco é conhecido sobre a importância desses neurônios sobre o controle vesical.

The micturition control, despite the apparent simplicity in its functioning, shows several levels of relative complexity. In conscious and unconscious states, it involves the activity of peripheral nerves, the sacral spinal cord, and the central areas that constitute the medulla oblongata, pons, midbrain, and cerebral cortex. In this review, the main currently known central areas involved in the urinary storage and voiding are focused, as well as the entrainment of peripheral signals related to the lower urinary tract. Pubmed and Scielo databases were searched using the keywords related to central control of voiding and urine storage. The first portion of the brainstem that demonstrated relationship to voiding activity was the pons, particularly the pontine micturition center (PMC).It is a point of convergence pro-stimuli and anti-urination and its main function is the command center for starting and harmonizing the bladder emptying. Different neurons of distinct regions fire after voiding, suggesting the existence of neurons signaling the initiation of detrusor relaxation. The periaqueductal gray matter is an important central area involved in the control of the lower urinary tract. It receives inhibitory modulation from posterior hypothalamic region, which is responsible for the defense mechanism (flight or fight). Other central structures such as the cerebral cortex, basal ganglia, and cerebellum have also been evidenced for modulating the micturition. Although medullary neurons are known for the integration of different somato-visceral signals and particularly for taking part in cardiovascular regulation, little is still known about the importance of those neurons in micturition control.

Central antioxidant therapy inhibits parasympathetic baroreflex control in conscious rats.

Baroreceptor reflex is an important system for neural control of blood pressure. Recently, reactive oxygen species (ROS) have been shown to play an important role in neuronal activity of central areas related to blood pressure control. The aim of this study was to investigate the effects elicited by ascorbic acid (AAC) and N-acetylcysteine (NAC) injections into the 4thV on the parasympathetic component of the baroreflex. Male Wistar rats were implanted with a stainless steel guide cannula into the 4thV. One day prior to the experiments, the femoral artery and vein were cannulated for pulsatile arterial pressure, mean arterial pressure and heart rate measurements and drug administration, respectively. After baseline recordings, the baroreflex was tested with a pressor dose of phenylephrine (PHE, 3 µg/kg, i.v.) and a depressor dose of sodium nitroprusside (SNP, 30 µg/kg, i.v.) before (control) and 5, 15, 30 and 60 min after AAC or NAC into the 4thV. Control PHE injection induced baroreflex-mediated bradycardia (-93 ± 13 bpm, n=7). Interestingly, after AAC injection into the 4thV, PHE injection produced a transient tachycardia at 5 (40 ± 23 bpm), 15 (26 ± 22 bpm) and 30 min (59 ± 21 bpm). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after AAC injection on 4thV (control: 151 ± 23bpm vs. 135 ± 18 bpm at 5 min after AAC, n=7). In the NAC treated group, PHE induced a reduction in reflex bradycardia at 5 min when compared to control (-11 ± 17 bpm vs. -83 ± 15 bpm, n=7). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after NAC injection on 4thV. The antioxidants AAC and NAC may act in the central nervous system affecting the parasympathetic component of the cardiac baroreflex.

Macrophage migration inhibitory factor in the paraventricular nucleus plays a major role in the sympathoexcitatory response to salt.

Central hyperosmotic stimulation (HS) evokes increases in sympathetic nerve activity mediated by activation of angiotensin type 1 receptors in the hypothalamic paraventricular nucleus (PVN). Macrophage inhibitory migration factor (MIF) is an intracellular inhibitory regulator of angiotensin type 1 receptor-mediated actions of angiotensin II within neurons of the PVN. MIF mediates its actions via its intrinsic thiol-protein oxidoreductase activity. We demonstrate that intracerebroventricular injection of hypertonic saline into Sprague-Dawley rats elicits a significant (≈112%) increase in MIF mRNA expression in the PVN. Next, we evaluated the effect of viral-mediated expression of either MIF or [C60S]-MIF (which lacks thiol-protein oxidoreductase activity) in the PVN on the sympathoexcitation evoked by HS. We used a decorticate, arterially perfused in situ preparation of male Wistar rats (60 to 80 g). HS was induced by raising perfusate osmolality from 290 to 380 milliosmoles for 40 seconds. Seven to 10 days before experiments, rats were injected bilaterally (500 nL per side) with 0.9% saline (control) or with adenoassociated virus to express MIF, [C60S]-MIF, or enhanced green fluorescent protein in the PVN. HS produced sympathoexcitation in both the 0.9% saline and enhanced green fluorescent protein groups (sympathetic nerve activity increase of +27±4% and +25±4%, respectively; P<0.05), an effect that was not observed in the MIF group (+4±5%). Conversely, the HS-induced increase in sympathetic nerve activity was potentiated in the [C60S]-MIF group (+45±6%; P<0.05). We propose that MIF acting within the PVN is a major counterregulator of HS-induced sympathoexcitation, an effect that depends on thiol-protein oxidoreductase activity.

Saphenofemoral arteriovenous fistula as hemodialysis access.

BACKGROUND: An upper limb arteriovenous (AV) fistula is the access of choice for haemodialysis (HD). There have been few reports of saphenofemoral AV fistulas (SFAVF) over the last 10-20 years because of previous suggestions of poor patencies and needling difficulties. Here, we describe our clinical experience with SFAVF. METHODS: SFAVFs were evaluated using the following variables: immediate results, early and late complications, intraoperative and postoperative complications (up to day 30), efficiency of the fistula after the onset of needling and complications associated to its use. RESULTS: Fifty-six SFAVF fistulas were created in 48 patients. Eight patients had two fistulas: 8 patent (16%), 10 transplanted (20%), 12 deaths (24%), 1 low flow (2%) and 20 thrombosis (39%) (first two months of preparation). One patient had severe hypotension during surgery, which caused thrombosis of the fistula, which was successfully thrombectomised, four thrombosed fistulae were successfully thrombectomised and revised on the first postoperative day. After 59 months of follow-up, primary patency was 44%. CONCLUSION: SFAVF is an adequate alternative for patients without the possibility for other access in the upper limbs, allowing efficient dialysis with good long-term patency with a low complication rate.

Anti-hypertensive drugs have different effects on ventricular hypertrophy regression: [review]

OBJECTIVES: There is a direct relationship between the regression of left ventricular hypertrophy (LVH) and a decreased risk of mortality. This investigation aimed to describe the effects of anti-hypertensive drugs on cardiac hypertrophy through a meta-analysis of the literature. METHODS: The Medline (via PubMed), Lilacs and Scielo databases were searched using the subject keywords cardiac hypertrophy, antihypertensive and mortality. We aimed to analyze the effect of anti-hypertensive drugs on ventricle hypertrophy. RESULTS: The main drugs we described were enalapril, verapamil, nifedipine, indapamina, losartan, angiotensin-converting enzyme inhibitors and atenolol. These drugs are usually used in follow up programs, however, the studies we investigated used different protocols. Enalapril (angiotensin-converting enzyme inhibitor) and verapamil (Ca++ channel blocker) caused hypertrophy to regress in LVH rats. The effects of enalapril and nifedipine (Ca++ channel blocker) were similar. Indapamina (diuretic) had a stronger effect than enalapril, and losartan (angiotensin II receptor type 1 (AT1) receptor antagonist) produced better results than atenolol (selective â1 receptor antagonist) with respect to LVH regression. CONCLUSION: The anti-hypertensive drugs induced various degrees of hypertrophic regression.