Water deprivation increases Fos expression in hypothalamic corticotropin-releasing factor neurons induced by right atrial distension in awake rats

Atrial mechanoreceptors, sensitive to stretch, contribute in regulating heart rate and intravascular volume. The information from those receptors reaches the nucleus tractus solitarius and then the paraventricular nucleus (PVN), known to have a crucial role in the regulation of cardiovascular function. Neurons in the PVN synthesize CRF, AVP, and oxytocin (OT). Stimulation of atrial mechanoreceptors was performed in awake rats implanted with a balloon at the junction of the superior vena cava and right atrium. Plasma ACTH, AVP, and OT concentrations and Fos, CRF, AVP, and OT immunolabeling in the PVN were determined after balloon inflation in hydrated and water-deprived rats. The distension of the balloon increased the plasma ACTH concentrations, which were higher in water-deprived than in hydrated rats (P < 0.05). In addition, the distension in the water-deprived group decreased plasma AVP concentrations (P < 0.05), compared with the respective control group. The distension increased the number of Fos- and double-labeled Fos/CRF neurons in the parvocellular PVN, which was higher in the water-deprived than in the hydrated group (P < 0.01). There was no difference in the Fos expression in magnocellular PVN neurons after distension in hydrated and water-deprived groups, compared with respective controls. In conclusion, parvocellular CRF neurons showed an increase of Fos expression induced by stimulation of right atrial mechanoreceptors, suggesting that CRF participates in the cardiovascular reflex adjustments elicited by volume loading. Activation of CRF neurons in the PVN by cardiovascular reflex is affected by osmotic stimulation.

Micro-Positron Emission Tomography in the Evaluation of Trypanosoma cruzi-Induced Heart Disease: Comparison with Other Modalities

Noninvasive assessment of cardiac structure and function is essential to understand the natural course of murine infection with Trypanosoma cruzi. Magnetic resonance imaging (MRI) and echocardiography have been used to monitor anatomy and function; positron emission tomography (PET) is ideal for monitoring metabolic events in the myocardium. Mice infected with T. cruzi (Brazil strain) were imaged 15-100 days post infection (dpi). Quantitative (18)F-FDG microPET imaging, MRI and echocardiography were performed and compared. Tracer ((18)F-FDG) uptake was significantly higher in infected mice at all days of infection, from 15 to 100 dpi. Dilatation of the right ventricular chamber was observed by MRI from 30 to 100 dpi in infected mice. Echocardiography revealed significantly reduced ejection fraction by 60 dpi. Combination of these three complementary imaging modalities makes it possible to noninvasively quantify cardiovascular function, morphology, and metabolism from the earliest days of infection through the chronic phase.

Adipose tissue as an endocrine organ

Adipose tissue is a highly active endocrine organ secreting a range of soluble products with both local and distant actions. These hormones have important roles in metabolism, reproduction, cardiovascular function and immunity. It is now evident that adipose endocrine function directly influences other organ systems, including the brain, liver and skeletal muscle. The endocrine function of adipose tissue is significantly regulated by nutritional status, and both are inextricably linked to the energy storage role of adipose tissue. This chapter highlights the endocrinology of adipose tissue by concentrating on functional aspects of the secreted products. The data of particular relevance to humans are highlighted, and areas in need of future research are suggested.

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 reflex 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 blood-gas 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 of arterial hypertension induced by N-nitro-L-arginine methyl ester (L-NAME) in which the interplay of these three reflexes is demonstrable.

Physical activity and pregnancy

SUMMARY : The traditional medical advice for pregnant women has been to reduce their physical activity (PA) levels. The advice was based on concerns that exercise could affect pregnancy outcomes by increasing core body temperature, by increasing the risk of maternal musculoskeletal injury and by altering the transplacental transport of oxygen and nutrients to maternal skeletal muscle rather than to the developing foetus. In the meantime, several studies have provided new information on adaptation of the pregnant woman and her foetus to moderate PA. New investigations have shown no adverse maternal or neonatal outcomes, abnormal foetal growth, increase in early pregnancy loss, or late pregnancy complications. Moreover, enrolment in moderate PA has proven to result in marked health benefits including improved maternal cardiovascular function, reduction of excessive weight gain and fat retention, less complicated labour, improved foetal stress tolerance and neurobehavioral maturation. In view of the beneficial effects, current recommendations encourage healthy pregnant women to engage in 30 minutes of moderate PA on most, if not all, days of the week. This thesis work addressed several questions. Firstly, it examined whether compliance with the recommended levels of PA during pregnancy results in better preparedness for the sudden physical exertion of labour and delivery. Secondly, it measured PA during pregnancy as compared to postpartum. Lastly, it assessed the influence of pre-pregnancy body mass index on gestational resting metabolic rate. Data collection was conducted on healthy women living in Switzerland during the third trimester of pregnancy and postpartum. Total and activity energy expenditure was assessed through 24-hour heart rate and accelerations recordings, and cardiovascular fitness through an individual step-test. Information related to pregnancy, labour and delivery was collected from medical records. The results indicate that a minimum 30 min of moderate PA per day during pregnancy are associated with better cardiovascular fitness and lower risk of operative delivery with no negative effects on maternal and foetal conditions (study 1). Despite these benefits, a substantial proportion of pregnant women (39%) living in Switzerland do not meet the PA recommendations. The decrease in activity related energy expenditure during pregnancy compared to postpartum was measured to be around 100 kcal/day (~13%), whereas the total energy expenditure was found to increase by 300 kcal/day (study 2). Thus, the energy cost of late pregnancy in Switzerland corresponds to 200 kca/day. These findings are based on average values of the study group. It should be noted, however, that large variations in individual energy expenditure may occur depending on the pre-pregnancy body mass index (study 3). When adjusted to body weight, gestational resting metabolic rate is significantly lower among women of high pre-pregnancy body mass index compared to women of normal or low pre-pregnancy body mass index. This can be explained by the fact that resting metabolic rate is primarily a function of fat-free mass, and when expressed per kg body weight, it decreases as the percentage of body fat increases. If energy intake is not modified appropriately in order to match lower energy cost per kg body weight in overweight and obese women it will result in positive energy balance, thus contributing to the current trend towards increasing adiposity in affluent society. The results of these studies go beyond the current state of knowledge on PA and pregnancy (study 4) and provide valid evidence to guide clinical practice. In view of the current epidemic of sedentary behaviour and obesity related pathology, the findings contribute new and reliable information to public health policies regarding the effects of PA in pregnancy, an important period of life for both mother and infant.

Expression and secretion of the atrial natriuretic peptide in human adipose tissue and preadipocytes.

OBJECTIVE: Atrial natriuretic peptide (ANP) is a secretory hormone displaying diuretic, natriuretic, and vasorelaxant activities. Recently, its lipolytic activity has been reported. Since the expression of ANP in adipose tissue has not been documented, we used real-time reverse transcriptase polymerase chain reaction (RT-PCR) to investigate the expression of ANP in human adipose tissue and preadipocytes. RESEARCH METHODS AND PROCEDURES: RNA was extracted from the human adipose tissue of severely obese premenopausal women as well as from human preadipocytes. For human preadipocytes, two cell systems were investigated: the human preadipose immortalized (Chub-S7) cells, a well-characterized human preadipose cell line, and primary preadipocytes derived from the stromal vascular fraction of the human adipose tissue. We measured the mRNA of ANP, of corin (a transmembrane serine protease involved in the conversion of pro-ANP to ANP) and of uncoupling protein 2 (UCP2; a control gene known to be ubiquitously expressed). The expression of ANP was also investigated using immunofluorescence and radioimmunoassay in Chub-S7 cells and human primary preadipocytes in culture. RESULTS: Our results indicate that ANP and corin are expressed at the mRNA level in human adipose tissue and preadipocytes. Immunofluorescence experiments demonstrated that pro-ANP was expressed in Chub-S7 cells. In addition, ANP secretion could be measured in Chub-S7 cells and human primary preadipocytes in culture. Rosiglitazone, a selective peroxisome proliferator-activated receptor type gamma (PPAR-gamma) agonist promoting adipocyte differentiation, was found to modulate both ANP expression and secretion in preadipocytes. DISCUSSION: Our findings suggest the existence of an autocrine/paracrine system for ANP in the human adipose tissue whose implications in lipolysis and cardiovascular function need to be further explored.

No development of hypertension in the hyperuricemic liver-Glut9 knockout mouse.

Urate is the metabolic end point of purines in humans. Although supra-physiological plasma urate levels are associated with obesity, insulin resistance, dyslipidemia, and hypertension, a causative role is debated. We previously established a mouse model of hyperuricemia by liver-specific deletion of Glut9, a urate transporter that provides urate to the hepatocyte enzyme uricase. These LG9 knockout mice show mild hyperuricemia (120 μmol/l), which can be further increased by the urate precursor inosine. Here, we explored the role of progressive hyperuricemia on the cardiovascular function. Arterial blood pressure and heart rate were periodically measured by telemetry over 6 months in LG9 knockout mice supplemented with incremental amounts of inosine in a normal chow diet. This long-term inosine treatment elicited a progressive increase in uricemia up to 300 μmol/l; however, it did not modify heart rate or mean arterial blood pressure in LG9 knockout compared with control mice. Inosine treatment did not alter cardiac morphology or function measured by ultrasound echocardiography. However, it did induce mild renal dysfunction as revealed by higher plasma creatinine levels, lower glomerular filtration rate, and histological signs of chronic inflammation and fibrosis. Thus, in LG9 knockout mice, inosine-induced hyperuricemia was not associated with hypertension despite partial renal deficiency. This does not support a direct role of urate in the control of blood pressure.

Alpha- and gamma-melanocyte stimulating hormones in obesity. A study of the key central areas of metabolic regulation

The melanocortin system is an important regulator of feeding, energy metabolism,and cardiovascular function and it consists of the pro-opiomelanocortin (POMC) derived melanocyte stimulating hormones (α-, β- and γ-MSH) and their endogenous melanocortin receptors, MC1R to MC5R. In the hypothalamus, α-MSH reduces food intake, and increases energy expenditure and sympathetic tone by binding to MC4R. Mutations affecting the MC4R gene lead to obesity in mammals. On the other hand, the metabolic effects of MC3R stimulation using agonists such as the endogenously expressed γ-MSH have been less extensively explored. The main objective of this study was to investigate the long-term effects of increased melanocortin tone in key areas of metabolic regulation in the central nervous system (CNS) in order to investigate the sitespecific roles of both α-MSH and γ-MSH. The aim was to stereotaxically induce local overexpression of single melanocortin peptides using lentiviral vectors expressing α-MSH (LVi-α-MSH-EGFP) and γ-MSH (LVi-γ-MSH-EGFP). The lentiviral vectors were shown to produce a long-term overexpression and biologically active peptides in cell-based assays. The LVi-α-MSHEGFP was targeted to the arcuate nucleus in the hypothalamus of diet induced obese mice where it reduced weight gain and adiposity independently of food intake. When the nucleus tractus solitarus in the brainstem was targeted, the LVi-α-MSH-EGFP treatment was shown to cause a small decrease in adiposity, which did not impact weight development. However, the α-MSH treatment increased heart rate, which was attenuated by adrenergic receptor blockade indicative of increased sympathetic activity. The LVi-γ-MSH-EGFP was targeted to the hypothalamus where it decreased fat mass in mice eating the standard diet, but the effect was abated if animals consumed a high-fat Western type diet. When the diet induced obese mice were subjected again to the standard diet, the LVi-γ-MSH-EGFP treated animals displayed increased weight loss and reduced adiposity. These results indicate that the long-term central anti-obesity effects of α-MSH are independent of food intake. In addition, overexpression of α-MSH in the brain stem efficiently blocked the development of adiposity, but increased sympathetic tone. The evidence presented in this thesis also indicates that selective MC3R agonists such as γ-MSH could be potential therapeutics in combination with low fat diets.

Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats

Several investigators have demonstrated that streptozotocin (STZ) diabetes induces changes in the autonomic control of the cardiovascular system. Changes in cardiovascular function may be related to peripheral neuropathy. The aim of the present study was to analyze changes in heart rate (HR) and arterial pressure (AP) as well as baroreflex and chemoreflex sensitivity in STZ-induced diabetic male Wistar rats (STZ, 50 mg/kg, iv, 15 days). Intra-arterial blood pressure signals were obtained for control and diabetic rats (N = 9, each group). Data were processed in a data acquisition system (CODAS, 1 kHz). Baroreflex sensitivity was evaluated by measuring heart rate changes induced by arterial pressure variation produced by phenylephrine and sodium nitroprusside injection. Increasing doses of potassium cyanide (KCN) were used to evaluate bradycardic and pressor responses evoked by chemoreflex activation. STZ induced hyperglycemia (447 ± 49 vs 126 ± 3 mg/dl), and a reduction in AP (99 ± 3 vs 118 ± 2 mmHg), resting HR (296 ± 11 vs 355 ± 16 bpm) and plasma insulin levels (16 ± 1 vs 57 ± 11 µU/ml). We also observed that the reflex bradycardia (-1.68 ± 0.1 vs -1.25 ± 0.1 bpm/mmHg, in the diabetic group) and tachycardia (-3.68 ± 0.5 vs -1.75 ± 0.3 bpm/mmHg, in the diabetic group) produced by vasopressor and depressor agents were impaired in the diabetic group. Bradycardia evoked by chemoreflex activation was attenuated in diabetic rats (control: -17 ± 1, -86 ± 19, -185 ± 18, -208 ± 17 vs diabetic: -7 ± 1, -23 ± 5, -95 ± 13, -140 ± 13 bpm), as also was the pressor response (control: 6 ± 1, 30 ± 7, 54 ± 4, 59 ± 5 vs diabetic: 6 ± 1, 8 ± 2, 33 ± 4, 42 ± 5 mmHg). In conclusion, the cardiovascular responses evoked by baroreflex and chemoreflex activation are impaired in diabetic rats. The alterations of cardiovascular responses may be secondary to the autonomic dysfunction of cardiovascular control

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 reflex 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 blood-gas 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 of arterial hypertension induced by N-nitro-L-arginine methyl ester (L-NAME) in which the interplay of these three reflexes is demonstrable

The physiological role of AT1 receptors in the ventrolateral medulla

Neurons in the rostral and caudal parts of the ventrolateral medulla (VLM) play a pivotal role in the regulation of sympathetic vasomotor activity and blood pressure. Studies in several species, including humans, have shown that these regions contain a high density of AT1 receptors specifically associated with neurons that regulate the sympathetic vasomotor outflow, or the secretion of vasopressin from the hypothalamus. It is well established that specific activation of AT1 receptors by application of exogenous angiotensin II in the rostral and caudal VLM excites sympathoexcitatory and sympathoinhibitory neurons, respectively, but the physiological role of these receptors in the normal synaptic regulation of VLM neurons is not known. In this paper we review studies which have defined the effects of specific activation or blockade of these receptors on cardiovascular function, and discuss what these findings tell us with regard to the physiological role of AT1 receptors in the VLM in the tonic and phasic regulation of sympathetic vasomotor activity and blood pressure.

Perinatal development and adult blood pressure

A growing body of evidence supports the concept of fetal programming in cardiovascular disease in man, which asserts that an insult experienced in utero exerts a long-term influence on cardiovascular function, leading to disease in adulthood. However, this hypothesis is not universally accepted, hence animal models may be of value in determining potential physiological mechanisms which could explain how fetal undernutrition results in cardiovascular disease in later life. This review describes two major animal models of cardiovascular programming, the in utero protein-restricted rat and the cross-fostered spontaneously hypertensive rat. In the former model, moderate maternal protein restriction during pregnancy induces an increase in offspring blood pressure of 20-30 mmHg. This hypertensive effect is mediated, in part, by fetal exposure to excess maternal glucocorticoids as a result of a deficiency in placental 11-ß hydroxysteroid dehydrogenase type 2. Furthermore, nephrogenesis is impaired in this model which, coupled with increased activity of the renin-angiotensin system, could also contribute to the greater blood pressure displayed by these animals. The second model discussed is the cross-fostered spontaneously hypertensive rat. Spontaneously hypertensive rats develop severe hypertension without external intervention; however, their adult blood pressure may be lowered by 20-30 mmHg by cross-fostering pups to a normotensive dam within the first two weeks of lactation. The mechanisms responsible for this antihypertensive effect are less clear, but may also involve altered renal function and down-regulation of the renin-angiotensin system. These two models clearly show that adult blood pressure is influenced by exposure to one of a number of stimuli during critical stages of perinatal development.

Role of sensory nervous system vasoactive peptides in hypertension

The goal of the present research was to elucidate the roles and mechanisms by which the sensory nervous system, through the actions of potent vasodilator neuropeptides, regulates cardiovascular function in both the normal state and in the pathophysiology of hypertension. The animal models of acquired hypertension studied were deoxycorticosterone-salt (DOC-salt), subtotal nephrectomy-salt (SN-salt), and Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertension during pregnancy in rats. The genetic model was the spontaneously hypertensive rat (SHR). Calcitonin gene-related peptide (CGRP) and substance P (SP) are potent vasodilating neuropeptides. In the acquired models of hypertension, CGRP and SP play compensatory roles to buffer the blood pressure (BP) increase. Their synthesis and release are increased in the DOC-salt model but not in the SN-salt model. This suggests that the mechanism by which both models lower BP in SN-salt rats is by increased vascular sensitivity. CGRP functions in a similar manner in the L-NAME model. In the SHR, synthesis of CGRP and SP is decreased. This could contribute to the BP elevation in this model. The CGRP gene knockout mouse has increased baseline mean arterial pressure. The long-term synthesis and release of CGRP is increased by nerve growth factor, bradykinin, and prostaglandins and is decreased by alpha2-adrenoreceptor agonists and glucocorticoids. In several animal models, sensory nervous system vasoactive peptides play a role in chronic BP elevation. In the acquired models, they play a compensatory role. In the genetic model, their decreased levels may contribute to the elevated BP. The roles of CGRP and SP in human hypertension are yet to be clarified.

Is persistent hypotension after transient cardiogenic shock associated with an inflammatory response?

We evaluated the recovery of cardiovascular function after transient cardiogenic shock. Cardiac tamponade was performed for 1 h and post-shock data were collected in 5 domestic large white female pigs (43 ± 5 kg) for 6 h. The control group (N = 5) was observed for 6 h after 1 h of resting. During 1 h of cardiac tamponade, experimental animals evolved a low perfusion status with a higher lactate level (8.0 ± 2.2 vs 1.9 ± 0.9 mEq/L), lower standard base excess (-7.3 ± 3.3 vs 2.0 ± 0.9 mEq/L), lower urinary output (0.9 ± 0.9 vs 3.0 ± 1.4 mL·kg-1·h-1), lower mixed venous saturation, higher ileum partial pressure of CO2-end tidal CO2 (EtCO2) gap and a lower cardiac index than the control group. Throughout the 6-h recovery phase after cardiac tamponade, tamponade animals developed significant tachycardia with preserved cardiac index, resulting in a lower left ventricular stroke work, suggesting possible myocardial dysfunction. Vascular dysfunction was present with persistent systemic hypotension as well as persistent pulmonary hypertension. In contrast, oliguria, hyperlactatemia and metabolic acidosis were corrected by the 6th hour. The inflammatory characteristics were an elevated core temperature and increased plasma levels of interleukin-6 in the tamponade group compared to the control group. We conclude that cardiovascular recovery after a transient and severe low flow systemic state was incomplete. Vascular dysfunction persisted up to 6 h after release of tamponade. These inflammatory characteristics may also indicate that inflammatory activation is a possible pathway involved in the pathogenesis of cardiogenic shock.

Purine nucleotides reduce superoxide production by nitric oxide synthase in a murine sepsis model

Sepsis involves a systemic inflammatory response of multiple endogenous mediators, resulting in many of the injurious and sometimes fatal physiological symptoms of the disease. This systemic activation leads to a compromised vascular response and endothelial dysfunction. Purine nucleotides interact with purinoceptors and initiate a variety of physiological processes that play an important role in maintaining cardiovascular function. The purpose of the present study was to investigate the effects of ATP on vascular function in a lipopolysaccharide (LPS) model of sepsis. LPS induced a significant increase in aortic superoxide production 16 h after injection. Addition of ATP to the organ bath incubation solution reduced superoxide production by the aortas of endotoxemic animals. Reactive Blue, an antagonist of the P2Y receptor, blocked the effect of ATP on superoxide production, and the nonselective P2Y agonist MeSATP inhibited superoxide production. Nitric oxide synthase (NOS) inhibition by L-NAME blocked vascular relaxation and reduced superoxide production in LPS-treated animals. In the presence of L-NAME there was no ATP effect on superoxide production. A vascular reactivity study showed that ATP increased maximal relaxation in LPS-treated animals compared to controls. The presence of ATP induced increases in Akt and endothelial NOS phosphorylated proteins in the aorta of septic animals. ATP reduces superoxide release resulting in an improved vasorelaxant response. Sepsis may uncouple NOS to produce superoxide. We showed that ATP through Akt pathway phosphorylated endothelial NOS and “re-couples” NOS function.