In clinical studies, sleep apnea is associated with hypertension, oxidative stress, and increased circulating endothelin-1 (ET-1). We previously developed a model of sleep apnea by exposing rats to eucapnic intermittent hypoxia (IH-C) during sleep, which increases both blood pressure and plasma levels of ET-1. Because similar protocols in mice increase tissue and plasma markers of oxidative stress, we hypothesized that IH-C generation of reactive oxygen species (ROS) contributes to the development of ET-1-dependent hypertension in IH-C rats. To test this, male Sprague-Dawley rats were instrumented with indwelling blood pressure telemeters and drank either plain water or water containing the superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, 1 mM). Mean arterial pressure (MAP) and heart rate (HR) were recorded for 3 control days and 14 treatment days with rats exposed 7 h/day to IH-C or air/air cycling (Sham). On day 14, MAP in IH-C rats treated with Tempol (107 ± 2.29 mmHg) was significantly lower than in untreated IH-C rats (118 ± 9 mmHg, P < 0.05). Tempol did not affect blood pressure in sham-operated rats (Tempol = 101 ± 3, water = 101 ± 2 mmHg). Immunoreactive ET-1 was greater in plasma from IH-C rats compared with plasma from shamoperated rats but was not different from Sham in Tempol-treated IH-C rats. Small mesenteric arteries from IH-C rats but not Tempol-treated IH-C rats had increased superoxide levels as measured by ferric cytochrome c reduction, lucigenin signaling, and dihydroethidium fluorescence. The data show that IH-C increases ET-1 production and vascular ROS levels and that scavenging superoxide prevents both. Thus oxidative stress appears to contribute to increases in ET-1 production and elevated arterial pressure in this rat model of sleep apnea-induced hypertension. Keywords Tempol; endothelinThe repeated episodes of cessation of breathing that occur during sleep apnea have been linked to the increased generation of reactive oxygen species (ROS) with an associated increase in cardiovascular morbidity (1). Since it is estimated that up to one in five adults in Western countries suffer from sleep apnea (36), this condition appears to be a significant cause of cardiovascular disease. Several longitudinal studies of sleep apnea patients conclude that the greatest health risk of sleep apnea is the increased incidence of cardiovascular disease (24,42), with the most consistent alteration being increased mean arterial pressure (MAP) (26,30). Thus almost 50% of people suffering from sleep apnea also suffer from hypertension (13), and it is of great relevance to better understand the role of oxidative stress in sleep apnea-associated hypertension.Repeated apneic episodes are reported to increase oxidative stress in sleep apnea patients (16,21), in animal models of sleep apnea (31, 41), and in cultured cells exposed to cyclical hypoxia (43). However, debate continues on the consequences of this elevated oxidative stress. One potential consequence is an incr...

Exposure to chronic intermittent hypoxia (CIH) yields persistent elevations in sympathetic nerve activity (SNA) and mean arterial pressure(MAP)with exaggerated sympathetic chemoreflexes. We examined the impact of CIH upon other sympathoexcitatory reflexes and a potential central mechanism underlying the altered regulation of SNA.Male Sprague-Dawley rats were exposed to CIH for 2 weeks (40 s at 6% O2 every 9 min, 8 h day⁻¹). After exposure to CIH, urethane-anaesthetized, vagotomized, ventilated, paralysed rats had significantly elevated MAP, splanchnic SNA, and rate of phrenic nerve discharge (PND; P<0.05). Elimination of SNA by ganglionic blockade produced a larger fall in MAP in rats exposed to CIH (P<0.05). Like acute hypoxia, stimulation of the sciatic nerve or the nasal mucosa evoked greater increases in SNA after exposure to CIH (P<0.05). In addition, acute hypoxia promoted exaggerated increases in PND amplitude after CIH (P<0.05). In contrast, the nasopharyngeal reflex evoked exaggerated increases in SNA during apnoea. These sympathoexcitatory reflexes are mediated by glutamatergic activation of the rostral ventrolateral medulla (RVLM), and accordingly, microinjections of glutamate into RVLM evoked larger increases in SNA after CIH (P<0.05). Paradoxically, none of these exaggerated acute rises in SNA was accompanied by enhanced pressor responses. Reduced adrenergic vascular reactivity may contribute to the blunted sympathetically mediated pressor responses, because bolus doses of phenylephrine evoked attenuated pressor responses after CIH (P<0.01).These data suggest exposure to CIH facilitates activation of SNA, potentially by changes within the RVLM. However, the exaggerated rises in SNA are not dependent upon stimulation of inspiratory drive. Although elevated SNA may contribute to CIH-induced hypertension, reduced adrenergic vascular reactivity buffers the cardiovascular impact of exaggerated acute rises in SNA.

Allahdadi KJ, Cherng TW, Pai H, Silva AQ, Walker BR, Nelin LD, Kanagy NL. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia. Am J Physiol Heart Circ Physiol 295: H434-H440, 2008. First published May 30, 2008 doi:10.1152/ajpheart.91477.2007.-We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ETA) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 Ϯ 2 to 137 Ϯ 4 mmHg; P Ͻ 0.005) but did not change in sham-exposed rats. The ETA receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol ⅐ kg Ϫ1 ⅐ day Ϫ1 sc for 14 days) prevented E-IHinduced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ETA receptor antagonist BQ-123 (10 M) but not by the ET type B (ET B) receptor antagonist BQ-788 (100 M). ETA receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ETB receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ETA receptors appears to elevate blood pressure in E-IHexposed rats. sleep apnea; BQ-123; BQ-788; mitochondrial ribonucleic acid OBSTRUCTIVE SLEEP APNEA is characterized by repeated upper airway obstruction during sleep and affects between 5% and 20% of the population (32). This syndrome of sleep-disordered breathing leads to episodic hypoxia and sleep deprivation. Recent epidemiological studies reveal that sleep apnea and other forms of sleep-disordered breathing increase the risk for hypertension and associated metabolic disorders (24). However, the mechanisms whereby sleep apnea and the associated eucapnic intermittent hypoxia (E-IH) cause systemic hypertension remain incompletely understood. Recent studies show that patients with sleep apnea have increased circulating levels of endothelin (ET)-1 (29, 42), a potent vasoconstrictor and mitogenic peptide implicated in the development of many forms of arterial hypertension (1). Furthermore, the synthesis of ET-1 is increased by hypoxia, shear stress, oxidative stress, and catecholamines, which are elevated in E-IH-exposed rats and sleep apnea (42, 47). We have previously described that both blood pressure and plasma ET-1 levels are incre...

Sleep apnea is characterized by increased sympathetic activity and is associated with systemic hypertension. Angiotensin (Ang) peptides have previously been shown to participate in the regulation of sympathetic tone and arterial pressure in the hypothalamic paraventricular nucleus (PVN) neurons. We investigated the role of endogenous Ang peptides within the PVN to control blood pressure in a rat model of sleep apnea-induced hypertension. Male Sprague Dawley rats (250g), instrumented with bilateral guide cannulae targeting the PVN, received chronic infusion of Ang antagonists (A-779, Ang-(1-7) antagonist; losartan and ZD7155, AT1 antagonists; PD123319, AT2 receptor antagonist, or saline vehicle). A separate group received an infusion of the GABAA receptor agonist (muscimol) to inhibit PVN neuronal activity independent of angiotensin receptors. After cannula placement, rats were exposed during their sleep period to eucapnic intermittent hypoxia (IH; nadir 5% O2; 5% CO2 to peak 21% O2; 0% CO2) 20 cycles/hour, 7 hours/day, for 14 days while mean arterial pressure (MAP) was measured by telemetry. In rats receiving saline, IH exposure significantly increased MAP (+12±2 mmHg vs Sham −2±1 mmHg P<0.01). Inhibition of PVN neurons with muscimol reversed the increase in MAP in IH rats (MUS: −9±4 mmHg vs vehicle +12±2 mmHg; P<0.01). Infusion of any of the Ang antagonists also prevented the rise in MAP induced by IH (A-779: −5±1 mmHg, losartan: −9±4 mmHg, ZD7155: −11±4 mmHg and PD123319: −4±3 mmHg; P<0.01). Our results suggest that endogenous Ang peptides acting in the PVN contribute to IH-induced increases in MAP observed in this rat model of sleep apnea-induced hypertension.

Abstract-In this study, we tested the hypothesis that angiotensin-(1-7) ] acting in the neurons of paraventricular hypothalamic nucleus (PVN) contributes to the maintenance of sympathetic activity and blood pressure. For this purpose, the effects of microinjection of the A-779, the receptor Mas antagonist, into the PVN on mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were evaluated. In rats anesthetized with urethane (1.2 to 1.4 g/kg IP), bilateral microinjections of A-779 (0.1 nmol) into the PVN resulted in a selective and significant decrease in RSNA (Ϫ26Ϯ6% versus Ϫ2Ϯ3% vehicle; saline 0.9%). Key Words: angiotensin antagonist Ⅲ angiotensin Ⅲ rats T he paraventricular hypothalamic nucleus (PVN) is 1 of the 5 major premotor neuron cell groups involved in the control of the sympathetic outflow. 1 The PVN influences sympathetic activity via direct projections to sympathetic preganglionic neurons or via a synaptic relay with the rostral ventrolateral medulla (RVLM), another group of presympathetic neurons that play a pivotal role in cardiovascular regulation. 1,2 Activation of PVN neurons by microinjection of the ␥-aminobutyric acid (GABA) receptor antagonist bicuculline increases arterial pressure and sympathetic activity in conscious 3 and anesthetized 4 rats. On the other hand, inhibition of PVN neurons by microinjection of muscimol, a powerful neuronal inhibitor, into the PVN decreases sympathetic activity and blood pressure. 5 This effect is more pronounced in the spontaneously hypertensive rat, suggesting that an imbalance in the sympathetic tonus generated from PVN neurons in this rat strain contributes to the elevated levels of blood pressure in this model of hypertension. 5 Findings from several previous studies indicate that peptides of the renin-angiotensin system (RAS) may act as important neuromodulators in different central sites involved in sympathetic output control, 6,7 and a dysfunction in the brain RAS may be implicated in the pathogenesis of hypertension. 6 Angiotensin-(1-7) [Ang-(1-7)] is now considered a biologically active peptide of the RAS family. 8 Many of the Ang-(1-7) actions are mediated primarily through the recently described receptor Mas 9 and are selectively blocked by its specific antagonist A-779. 10 Several studies suggest that apart from its peripheral actions, Ang-(1-7) exerts actions in central sites involved in cardiovascular control, 8,11 including nucleus of solitary tract, 12,13 RVLM, [14][15][16][17] In fact, the first biological action described for Ang-(1-7) showed that this peptide was a potent secretagogue of arginine vasopressin in hypothalamic-hypophyseal explants. 19 Immunoreactive staining for Ang-(1-7) is present in the PVN, 20 specifically in the lateral parvocellular and posterior magnocellular subdivisions, 21 and endogenous Ang-(1-7) in the rat hypothalamus is present in concentrations comparable to angiotensin I (Ang I) and Ang II. 22 Previous studies showed that microiontophoretic application of Ang-(1-7) into t...

Previous evidence indicates that a balance between inhibitory gabaergic and excitatory angiotensinergic factors in the PVN is important for cardiovascular control. We investigated the cardiovascular response evoked from activation or blockade of GABA(A) receptors in the paraventricular nucleus (PVN), in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Brain Ang II and Ang-(1-7) levels were also determined. In functional experiments, TGR(ASrAOGEN) and Sprague-Dawley rats (SD, control) were anesthetized with urethane and blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. Brain Ang II and Ang-(1-7) levels were largely reduced in TGR(ASrAOGEN) compared with SD rats. Inhibition of PVN neurons with the GABA(A) agonist, muscimol (1 nmol/100 nL), resulted in an attenuated fall in all cardiovascular variables in TGR(ASrAOGEN) compared with SD rats. This difference was particularly pronounced in HR (TGR Mus -23±6 bpm vs. -77±9 bpm SD Mus; P<0.05) and RSNA (TGR -3±10% vs.-29±8% SD; P<0.05). Furthermore, the sympathetic response evoked by blockade of GABA(A) receptors in the PVN of TGR(ASrAOGEN) was also largely suppressed. The present data indicate that the sympathetic outflow mediated by PVN neurons under basal conditions is suppressed in TGR(ASrAOGEN) rats corroborating the functional significance of brain angiotensin production in the central regulation of sympathetic output to the cardiovascular system.

| Introduction: Primary dysmenorrhea is characterized as a pelvic pain associated with other symptoms. It is a frequent gynecological complaint that can cause a drop in yield and productivity in affected women, being commonly treated by self-medication despite the side effects that this practice can trigger. Objective: To analyze the efficacy of physical exercises in the treatment of primary dysmenorrhea. symptons. Materials and methods: This systematic review was conducted according to the PRISMA methodology. Randomized controlled clinical trials were searched in PEDro, PubMed, LILACS, SciELO, MEDLINE and CENTRAL databases. The methodological quality os the selected articles was evaluated using the PEDro scale. Results: Five articles were included for analysis with a total sample of 436 women with primary dysmenorrhea symptoms who were submitted or not to a protocol of physical exercises. The overall mean score resulting from the methodological evaluation of the studies was 4.6. All the evaluated articles presented beneficial effects of the practice of physical exercises in the treatment of primary dysmenorrhoea, for at least one evaluated variable. Conclusion: There were identified evidences showing that the practice of physical exercises may reduce the symptoms associated with dysmenorrhea, therefore it can be considered as an effective treatment on detriment of the use of drugs. The development of a more reliable and assertive evaluation instrument that covers the totality of symptoms related to primary dysmenorrhea is necessary to contribute to the elaboration of future standardized studies which allows an analysis and comparison of results in a more consistent manner.Keywords: Dysmenorrhea; Exercise; Review. RESUMO | Introdução: A dismenorreia primária é caracterizada como uma dor pélvica associada a outros sintomas. É uma queixa ginecológica frequente que pode ocasionar queda de rendimento e produtividade nas mulheres afetadas, sendo comumente tratada por automedicações apesar dos efeitos colaterais que esta prática pode desencadear. Objetivo: Analisar a eficácia dos exercícios físicos no tratamento da sintomatologia da dismenorreia primária. Materiais e métodos: Trata-se de um estudo de revisão sistemática, conduzido conforme a metodologia PRISMA. Artigos classificados como ensaios clínicos randomizados controlados foram pesquisados nas bases de dados PEDro, PubMed, LILACS, SciELO, MEDLINE e CENTRAL. Os artigos foram avaliados quanto a sua qualidade metodológica através da escala PEDro. Resultados: Cinco artigos foram incluídos para análise com amostra total de 436 mulheres com sintomas dismenorreicos que foram submetidas ou não a um protocolo de exercícios físicos. O escore médio geral, resultante da avaliação da qualidade dos estudos, foi de 4,6. Todos os artigos avaliados apresentaram resultados benéficos advindos da prática de exercícios físicos no tratamento da dismenorreia primária, para pelo menos uma variável avaliada. Conclusão: Identificaram-se evidências de que a prática de exercícios...

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