New Insights Into the Role of Inflammation in the Brain in Heart Failure.

Heart failure is a growing medical problem. Although the underlying aetiology of heart failure differs according to the phenotype, there are some common characteristics observed in patients with heart failure. These include an increased sympathetic nerve activity, an activated renin-angiotensin system, and inflammation. The mechanisms mediating the increased sympathetic activity are not completely understood but the central nervous system plays a major role. Activation of the renin-angiotensin system plays an active role in the remodelling of the heart and in fluid and electrolyte imbalance. The presence of a central renin-angiotensin system means that locally produced angiotensin in the brain may also play a key role in autonomic dysfunction seen in heart failure. Markers of inflammation in the heart and in the circulation are observed in patients diagnosed with heart failure. Circulating pro-inflammatory cytokines can also influence cardiac function further afield than just locally in the heart including actions within the brain to activate the sympathetic nervous system. Preclinical evidence suggests that targeting the pro-inflammatory cytokines would be a useful therapy to treat heart failure. Most clinical studies have been disappointing. This mini-review suggests that pro-inflammatory cytokines in the brain play a key role and there is a problem associated with access of effective doses of the drugs to the site of action in the brain. The recent advances in nanotechnology delivery techniques may provide exciting future technology to investigate the role of specific pro-inflammatory mediators as novel targets within the brain in the treatment of heart failure.

The Enigma of the Adrenarche: Identifying the Early Life Mechanisms and Possible Role in Postnatal Brain Development.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland-the adrenarche-and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.

Cardiovascular and Metabolic Crosstalk in the Brain: Leptin and Resistin.

Leptin and resistin are cytokines whose plasma levels correlate with adiposity. Leptin is a hormone synthesised and released from adipocytes and can be transported into the brain. Resistin is produced in adipocytes in rodents and in macrophages in humans, particularly macrophages that have infiltrated adipose tissue. Both hormones can act within the brain to influence sympathetic nerve activity. Leptin appears to have a generalised sympatho-excitatory actions whilst resistin appears to increase sympathetic nerve activity affecting the cardiovascular system but inhibits sympathetic nerve activity to brown adipose tissue, which contrasts with leptin. Since both hormones can be elevated in conditions of metabolic dysfunction, interactions/crosstalk between these two hormones in the brain is a real possibility. This review describes the current knowledge regarding such crosstalk within the central nervous system. The evidence suggests that with respect to sympathetic nerve activity, crosstalk between leptin and resistin can elicit enhanced sympatho-excitatory responses to the kidneys. In contrast, with respect to food intake, resistin has weaker effects, but in regard to insulin secretion and thermogenesis, leptin and resistin have opposing actions. Thus, in conditions in which there is increased resistin and leptin levels, the result of crosstalk in the central nervous system could contribute to worse cardiovascular and metabolic complications.

Students from a large Australian university use Twitter to identify difficult course concepts to review during face-to-face lectorial sessions.

Engaging undergraduate students in large classes is a constant challenge for many lecturers, as student participation and engagement can be limited. This is a concern since there is a positive correlation between increased engagement and student success. The lack of student feedback on content delivery prevents lecturers from identifying topics that would benefit students if reviewed. Implementing novel methods to engage the students in course content and create ways by which they can inform the lecturer of the difficult concepts is needed to increase student success. In the present study, we investigated the use of Twitter as a scalable approach to enhance engagement with course content and peer-to-peer interaction in a large course. In this pilot study, students were instructed to tweet the difficult concepts identified from content delivered by videos. A software program automatically collected and parsed the tweets to extract summary statistics on the most common difficult concepts, and the lecturer used the information to prepare face-to-face (F2F) lectorial sessions. The key findings of the study were 1) the uptake of Twitter (i.e., registration on the platform) was similar to the proportion of students who participated in F2F lectorials, 2) students reviewed content soon after delivery to tweet difficult concepts to lecturer, 3) Twitter increased engagement with lecturers, 4) the difficult concepts were similar to previous years, yet the automated gathering of Twitter data was more efficient and time saving for the lecturer, and 5) students found the lectorial review sessions very valuable.

The Carotid Body a Common Denominator for Cardiovascular and Metabolic Dysfunction?

The carotid body is a highly vascularized organ designed to monitor oxygen levels. Reducing oxygen levels in blood results in increased activity of the carotid body cells and reflex increases in sympathetic nerve activity. A key contributor to elevated sympathetic nerve activity in neurogenic forms of hypertension is enhanced peripheral chemoreceptor activity. Hypertension commonly occurs in metabolic disorders, like obesity. Such metabolic diseases are serious global health problems. Yet, the mechanisms contributing to increased sympathetic nerve activity and hypertension in obesity are not fully understood and a better understanding is urgently required. In this review, we examine the literature that suggests that overactivity of the carotid body may also contribute to metabolic disturbances. The purine ATP is an important chemical mediator influencing the activity of the carotid body and the role of purines in the overactivity of the carotid body is explored. We will conclude with the suggestion that tonic overactivity of the carotid body may be a common denominator that contributes to the hypertension and metabolic dysfunction seen in conditions in which metabolic disease exists such as obesity or insulin resistance induced by high caloric intake. Therapeutic treatment targeting the carotid bodies may be a viable treatment since translation to the clinic could be more easily performed than expected via repurposing antagonists of purinergic receptors currently in clinical practice, and the use of other minimally invasive techniques that reduce the overactivity of the carotid bodies which may be developed for such clinical use.

Central Administration of Insulin Combined With Resistin Reduces Renal Sympathetic Nerve Activity in Rats Fed a High Fat Diet.

Insulin receptors are widely distributed in the central nervous system and their activation by insulin elicits renal sympatho-excitatory effects. Resistin, an adipokine, promotes resistance to the metabolic effects of insulin. Resistin also induces increases in renal sympathetic nerve activity (RSNA) by acting in the brain, but whether it can influence insulin's actions on RSNA is unknown. In the present study we investigated, in male Sprague-Dawley rats (7-8 weeks of age), the effects of central administration of insulin combined with resistin on RSNA following a normal diet (ND) and a high fat diet (HFD) (22% fat), since HFD can reportedly attenuate insulin's actions. RSNA, mean arterial pressure (MAP) and heart rate (HR) responses were monitored and recorded before and for 180 min after intracerebroventricular injection of saline (control) (n = 5 HFD and ND), resistin (7 µg; n = 4 ND, n = 5 HFD), insulin (500 mU; n = 6 ND, n = 5 HFD), and the combination of both resistin and insulin (n = 7 ND, n = 5 HFD). The key finding of the present study was that when resistin and insulin were combined there was no increase in RSNA induced in rats fed a normal diet or the high fat diet. This contrasted with the sympatho-excitatory RSNA effects of the hormones when each was administered alone in rats fed the ND and the HFD.

A tale of two steroids: The importance of the androgens DHEA and DHEAS for early neurodevelopment.

DHEA and DHEAS are neuroactive neurosteroids that interact with several major receptor systems in the brain, including sigma (σ), glutamate, and GABA-A receptors. It has been recognized as early as 1952, that the loss of DHEA/DHEAS in adult life is associated with neuropsychiatric disorders (eg schizophrenia, depression). However, the mechanistic role for DHEA/DHEAS in any of these domains remains speculative, not the least because the presence of these androgens in the adrenal gland and brain is largely confined to humans and only some non-human primates. DHEA and DHEAS are dynamically regulated from before birth and before the onset of puberty, and therefore an understanding of the synthesis, regulation, and functions of this important androgen pathway warrants attention. Here, we draw attention to the possible modulating influence of DHEA/DHEAS in early brain development from fetal life to the remarkable increase of these steroids in early childhood - the adrenarche. We propose that the pre-pubertal DHEA/DHEAS surge plays a key role in modulating early brain development, perhaps by prolonging brain plasticity during childhood to allow the pre-adolescent brain to adapt and re-wire in response to new, and ever-changing social challenges. Nonetheless, the aetiology of neurodevelopmental phenomena in relation to DHEA/DHEAS synthesis and action cannot be easily studied in humans due to the obvious ethical restrictions on mechanistic studies, the uncertainty of predicting the future mental characteristics of individuals, and the difficulty of conducting retrospective investigations based on pre-birth and/or neonatal complications. We discuss new opportunities for animal studies to resolve these important questions.

DHEA in Prenatal and Postnatal Life: Implications for Brain and Behavior.

Dehydroepiandrosterone (DHEA) and its sulfated congener (DHEAS) are the principal C19 steroid produced by the adrenal gland in many mammals, including humans. It is secreted in high concentrations during fetal life, but synthesis decreases after birth until, in humans and some other primates, there is a prepubertal surge of DHEA production by the adrenal gland-a phenomenon known as adrenarche. There remains considerable uncertainty about the physiological role of DHEA and DHEAS. Moreover, the origin of the trophic drives that determine the waxing and waning of DHEA synthesis are poorly understood. These gaps in knowledge arise in some measure from the difficulty of understanding mechanistic determinants from observations made opportunistically in humans and primates, and have stimulated a search for other suitable species that exhibit adrenarche- and adrenopause-like changes of adrenal function. DHEA and DHEAS are clearly neuroactive steroids with actions at several neurotransmitter receptors; indeed, DHEA is now known to be also synthesized by many parts of the brain, and this capacity undergoes ontogenic changes, but whether this is dependent or independent of the changes in adrenal synthesis is unknown. In this chapter we review key contributions to this field over the last 50+ years, and speculate on the importance of DHEA for the brain, both during development and for maturation and aging of cerebral function and behavior.

High Fat Diet Decreases Neuronal Activation in the Brain Induced by Resistin and Leptin.

Resistin and leptin are adipokines which act in the brain to regulate metabolic and cardiovascular functions which in some instances are similar, suggesting activation of some common brain pathways. High-fat feeding can reduce the number of activated neurons observed following the central administration of leptin in animals, but the effects on resistin are unknown. The present work compared the distribution of neurons in the brain that are activated by centrally administered resistin, or leptin alone, and, in combination, in rats fed a high fat (HFD) compared to a normal chow diet (ND). Immunohistochemistry for the protein, Fos, was used as a marker of activated neurons. The key findings are (i) following resistin or leptin, either alone or combined, in rats fed the HFD, there were no significant increases in the number of activated neurons in the paraventricular and arcuate nuclei, and in the lateral hypothalamic area (LHA). This contrasted with observations in rats fed a normal chow diet; (ii) in the OVLT and MnPO of HFD rats there were significantly less activated neurons compared to ND following the combined administration of resistin and leptin; (iii) In the PAG, RVMM, and NTS of HFD rats there were significantly less activated neurons compared to ND following resistin. The results suggest that the sensitivity to resistin in the brain was reduced in rats fed a HFD. This has similarities with leptin but there were instances where there was reduced sensitivity to resistin with no significant effects following leptin. This suggests diet influences neuronal effects of resistin.

Central leptin and resistin combined elicit enhanced central effects on renal sympathetic nerve activity.

NEW FINDINGS: What is the central question of this study? Leptin and resistin act centrally to increase renal sympathetic nerve activity (RSNA). We investigated whether a combination of resistin and leptin could induce a greater response than either alone. We also used Fos protein to quantify the number of activated neurons in the brain. What is the main finding and its importance? A combination of leptin and resistin induced a greater increase in RSNA than either hormone alone. This was correlated with a greater number of activated neurons in the arcuate nucleus than with either hormone alone. Leptin and resistin act centrally to increase renal sympathetic nerve activity (RSNA). We investigated whether a combination of resistin and leptin could induce a greater response than either alone. Mean arterial pressure, heart rate and RSNA were recorded before and for 3 h after intracerebroventricular saline (control; n = 5), leptin (7 µg; n = 5), resistin (7 µg; n = 4) and leptin administered 15 min after resistin (n = 6). Leptin alone and resistin alone significantly increased RSNA (74 ± 17 and 50 ± 14%, respectively; P < 0.0001 compared with saline). When leptin and resistin were combined, there was a significantly greater increase in RSNA (163 ± 23%) compared with either hormone alone (P < 0.0001). Maximal responses of mean arterial pressure and heart rate were not significantly different between groups. We also used Fos protein to quantify the number of activated neurons in the brain. Compared with controls, there were significant increases in numbers of Fos-positive neurons in the arcuate and hypothalamic paraventricular nuclei when leptin or resistin was administered alone or when they were combined, and in the lamina terminalis when leptin and resistin were combined. Only in the arcuate nucleus was the increase significantly greater compared with either hormone alone. The findings show that a combination of leptin and resistin induces a greater RSNA increase and a greater number of activated neurons in the arcuate nucleus than with either hormone alone. Given that leptin makes an important contribution to the elevated RSNA observed in obese and overweight conditions, the increased concentrations of leptin and resistin may mean that the contribution of leptin to the elevated RSNA in those conditions is enhanced.

Central Administration of Insulin and Leptin Together Enhance Renal Sympathetic Nerve Activity and Fos Production in the Arcuate Nucleus.

There is considerable interest in the central actions of insulin and leptin. Both induce sympatho-excitation. This study (i) investigated whether centrally administered leptin and insulin together elicits greater increases in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) than when given alone, and (ii) quantified the number of activated neurons in brain regions influencing SNA, to identify potential central sites of interaction. In anesthetised (urethane 1.4-1.6 g/kg iv) male Sprague-Dawley rats, RSNA, MAP, and HR were recorded following intracerebroventricular (ICV) saline (control; n = 5), leptin (7 µg; n = 5), insulin (500 mU; n = 4) and the combination of leptin and insulin; (n = 4). Following leptin or insulin alone, RSNA was significantly increased (74 and 62% respectively). MAP responses were not significantly different between the groups. Insulin alone significantly increased HR. Leptin alone also increased HR but it was significantly less than following insulin alone (P < 0.005). When leptin and insulin were combined, the RSNA increase (124%) was significantly greater than the response to either alone. There were no differences between the groups in MAP responses, however, the increase in HR induced by insulin was attenuated by leptin. Of the brain regions examined, only in the arcuate nucleus did leptin and insulin together increase the number of Fos-positive cell nuclei significantly more than leptin or insulin alone. In the lamina terminalis and rostroventrolateral medulla, leptin and insulin together increased Fos, but the effect was not greater than leptin alone. The results suggest that when central leptin and insulin levels are elevated, the sympatho-excitatory response in RSNA will be greater. The arcuate nucleus may be a common site of cardiovascular integration.

Resistin, an Adipokine with Non-Generalized Actions on Sympathetic Nerve Activity.

The World Health Organization has called obesity a global epidemic. There is a strong association between body weight gain and blood pressure. A major determinant of blood pressure is the level of activity in sympathetic nerves innervating cardiovascular organs. A characteristic of obesity, in both humans and in animal models, is an increase in sympathetic nerve activity to the skeletal muscle vasculature and to the kidneys. Obesity is now recognized as a chronic, low level inflammatory condition, and pro-inflammatory cytokines are elevated including those produced by adipose tissue. The most well-known adipokine released from fat tissue is leptin. The adipokine, resistin, is also released from adipose tissue. Resistin can act in the central nervous system to influence the sympathetic nerve activity. Here, we review the effects of resistin on sympathetic nerve activity and compare them with leptin. We build an argument that resistin and leptin may have complex interactions. Firstly, they may augment each other as both are excitatory on sympathetic nerves innervating cardiovascular organs; In contrast, they could antagonize each other's actions on brown adipose tissue, a key metabolic organ. These interactions may be important in conditions in which leptin and resistin are elevated, such as in obesity.

Attenuation of microglial and neuronal activation in the brain by ICV minocycline following myocardial infarction.

Following myocardial infarction, microglia, the immune cells in the central nervous system, become activated in the hypothalamic paraventricular nucleus (PVN) suggesting inflammation in this nucleus. Little is known about other brain nuclei. In the present study, we investigated whether the rostral ventrolateral medulla (RVLM), the nucleus tractus solitarius (NTS) and the periaqueductal grey (PAG), regions known to have important cardiovascular regulatory functions, also show increased microglial activation and whether this coincides with increased neuronal activity. We also investigated whether minocycline inhibited microglial activation and whether this also affected neuronal activity and cardiac function. Compared to controls there was a significant increase in the proportion of activated microglia and neuronal activation in the PVN, RVLM, NTS and PAG, 12weeks following myocardial infarction (P<0.001). Intracebroventricular infusion of minocycline (beginning one week prior to infarction) significantly attenuated the increase in microglial activation by at least 50% in the PVN, RVLM, PAG and NTS, and neuronal activation was significantly reduced by 50% in the PVN and virtually abolished in the PAG, RVLM and NTS. Cardiac function (percent fractional shortening) was significantly reduced by 55% following myocardial infarction but this was not ameliorated by minocycline treatment. The results suggest that following myocardial infarction, inflammation occurs in brain nuclei that play key roles in cardiovascular regulation and that attenuation of this inflammation may not be sufficient to ameliorate cardiac function.

Effect of type 1 diabetes on the production and vasoactivity of hydrogen sulfide in rat middle cerebral arteries.

Hydrogen sulfide (H2S) is produced endogenously in vascular tissue and has both vasoregulation and antioxidant effects. This study examines the effect of diabetes-induced oxidative stress on H2S production and function in rat middle cerebral arteries. Diabetes was induced in rats with streptozotocin (50 mg/kg, i.v.). Middle cerebral artery function was examined using a small vessel myograph and superoxide anion generation measured using nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lucigenin-enhanced chemiluminescence. Cystathionine-γ-lyase (CSE) mRNA expression was measured via RT-PCR. Diabetic rats had elevated blood glucose and significantly reduced cerebral artery endothelial function. Maximum vasorelaxation to the H2S donor NaHS was unaffected in diabetic cerebral arteries and was elicited via a combination of K(+), Cl(-), and Ca(2+) channel modulation, although the contribution of Cl(-) channels was significantly less in the diabetic cerebral arteries. Vasorelaxation to the H2S precursor l-cysteine and CSE mRNA were significantly increased in diabetic cerebral arteries. Cerebral artery superoxide production was significantly increased in diabetes, but this increase was attenuated ex vivo by incubation with the H2S donor NaHS. These data confirm that cerebral artery endothelial dysfunction and oxidative stress occurs in diabetes. Endogenous H2S production and activity is upregulated in cerebral arteries in this model of diabetes. Vasorelaxation responses to exogenous H2S are preserved and exogenous H2S attenuates the enhanced cerebral artery generated superoxide observed in the diabetic group. These data suggest that upregulation of endogenous H2S in diabetes may play an antioxidant and vasoprotective role.

ERK1/2 in the brain mediates the effects of central resistin on reducing thermogenesis in brown adipose tissue.

We investigated the role of ERK1/2 in the brain on the effects of centrally administered resistin on thermogenesis. Resistin (7 µg) into anaesthetized rats significantly decreased brown adipose tissue temperature by 1.0 ± 0.4 °C (P < 0.005). This response was significantly attenuated by over 60% when ERK1/2 was inhibited by U0126 (7 µg) (P < 0.05). Resistin reduced uncoupling protein-1 mRNA expression (0.11 ± 0.01 vs 1.24 ± 0.85 resistin vs control respectively) and the expression of peroxisome proliferator-activated receptor gamma co-activator 1-α, but the effects were not statistically significant. The results suggest that ERK1/2 in the brain contributes to resistin's effects on thermogenesis.

A natural variant of obestatin, Q90L, inhibits ghrelin's action on food intake and GH secretion and targets NPY and GHRH neurons in mice.

BACKGROUND: Ghrelin and obestatin are two gut-derived peptides originating from the same ghrelin/obestatin prepropeptide gene (GHRL). While ghrelin stimulates growth hormone (GH) secretion and food intake and inhibits γ-aminobutyric-acid synaptic transmission onto GHRH (Growth Hormone Releasing Hormone) neurons, obestatin blocks these effects. In Humans, GHRL gene polymorphisms have been associated with pathologies linked to an unbalanced energy homeostasis. We hypothesized that one polymorphism located in the obestatin sequence (Q to L substitution in position 90 of the ghrelin/obestatin prepropeptide, rs4684677) may impact on the function of obestatin. In the present study, we tested the activity of native and Q90L obestatin to modulate ghrelin-induced food intake, GH secretion, cFos activity in GHRH and Neuropeptide Y (NPY) neurons and γ-aminobutyric-acid activity onto GHRH neurons. METHODOLOGY/PRINCIPAL FINDINGS: Food intake, GH secretion and electrophysiological recordings were assessed in C57BL/6 mice. cFos activity was measured in NPY-Renilla-GFP and GHRH-eGFP mice. Mice received saline, ghrelin or ghrelin combined to native or Q90L obestatin (30 nmol each) in the early light phase. Ghrelin stimulation of food intake and GH secretion varied considerably among individual mice with 59-77% eliciting a robust response. In these high-responders, ghrelin-induced food intake and GH secretion were reduced equally by native and Q90L obestatin. In contrast to in vivo observations, Q90L was slightly more efficient than native obestatin in inhibiting ghrelin-induced cFos activation within the hypothalamic arcuate nucleus and the nucleus tractus solitarius of the brainstem. After ghrelin injection, 26% of NPY neurons in the arcuate nucleus expressed cFos protein and this number was significantly reduced by co-administration of Q90L obestatin. Q90L was also more potent that native obestatin in reducing ghrelin-induced inhibition of γ-aminobutyric-acid synaptic transmission onto GHRH neurons. CONCLUSIONS/SIGNIFICANCE: These data support the hypothesis that Q90L obestatin partially blocks ghrelin-induced food intake and GH secretion by acting through NPY and GHRH neurons.

Effect of western and high fat diets on memory and cholinergic measures in the rat.

Recent evidence shows an association between obesity and cognitive decline. The present study aimed to determine whether a very high fat (60%) or western diet can affect working or spatial memory in rats and whether the diet-induced cognitive impairment is linked to the level of acetylcholine in the brain. Three groups of male Long Evans rats were fed either chow, western diet (21% fat, 0.15% cholesterol) or a high fat diet (60% fat) for 12 weeks (n=12 per group). Body weight, food intake and blood pressure were measured weekly. Behavioural testing, novel object recognition and Y-maze were carried out at 12 weeks. At the end of the study brain choline acetyltransferase and acetylcholinesterase levels were estimated. Results showed that consumption of a western diet for twelve weeks impaired a rat's spatial memory (p<0.05), and increased body weight, calorie intake, blood pressure and triglyceride levels. Conversely our high fat diet also impaired spatial memory (p<0.05) but this effect was independent of the rat's body weight or blood pressure. No significant changes in brain acetylcholine markers were observed. In conclusion, diets with higher fat content impaired hippocampal-dependant memory, even when hypertension and obesity are absent; however the mechanism is still unclear.

Sustained activation of microglia in the hypothalamic PVN following myocardial infarction.

Microglia are the immune cells in the central nervous system and can produce cytokines when they are activated by an insult or injury. In the present study, we investigated in detail the time frame of the activation of microglia in the hypothalamic paraventricular nucleus (PVN) following myocardial infarction in rats. Morphological changes and immunohistochemistry to detect CD11b (clone OX-42) were used to identify activated microglia. Compared to rats that had undergone sham surgical procedures, there was a significant increase of between 40 and 50% in the proportion of activated microglia in the PVN 4-16 weeks following myocardial infarction (P<0.001, One way ANOVA). At 24h or 1 week post myocardial infarction, however, there was no significant increase in the proportion of activated microglia. Echocardiography and haemodynamic parameters after myocardial infarction indicated significantly reduced left ventricular function. In conclusion, following myocardial infarction, activation of microglia in the PVN does not occur immediately but once manifested, activation is sustained. Thus, activated microglia may contribute to the chronic elevation in cytokine levels observed following myocardial infarction. Since cytokines elicit sympatho-excitatory effects when locally microinjected into the PVN, activated microglia may contribute to the mechanisms mediating the chronic increase in sympathetic nerve activity in animals with reduced left ventricular function induced following myocardial infarction.

Hydrogen Sulfide in the RVLM and PVN has No Effect on Cardiovascular Regulation.

Hydrogen sulfide (H(2)S) is now recognized as an important signaling molecule and has been shown to have vasodilator and cardio-protectant effects. More recently it has been suggested that H(2)S may also act within the brain to reduce blood pressure (BP). In the present study we have demonstrated the presence of the H(2)S-producing enzyme, cystathionine-ß-synthase (CBS) in the rostral ventrolateral medulla (RVLM), and the hypothalamic paraventricular nucleus (PVN), brain regions with key cardiovascular regulatory functions. The cardiovascular role of H(2)S was investigated by determining the BP, heart rate (HR), and lumbar sympathetic nerve activity (LSNA) responses elicited by a H(2)S donor sodium hydrogen sulfide (NaHS) or inhibitors of CBS, microinjected into the RVLM and PVN. In anesthetized Wistar Kyoto rats bilateral microinjections of NaHS (0.2-2000 pmol/side) into the RVLM did not significantly affect BP, HR, or LSNA, compared to vehicle. Similarly, when the CBS inhibitors, amino-oxyacetate (AOA; 0.1-1.0 nmol/side) or hydroxylamine (HA; 0.2-2.0 nmol/side), were administered into the RVLM, there were no significant effects on the cardiovascular variables compared to vehicle. Microinjections into the PVN of NaHS, HA, and AOA had no consistent significant effects on BP, HR, or LSNA compared to vehicle. We also investigated the cardiovascular responses to NaHS microinjected into the RVLM and PVN in spontaneously hypertensive rats. Again, there were no significant effects on BP, HR, and LSNA. Together, these results suggest that H(2)S in the RVLM and PVN does not have a major role in cardiovascular regulation.