Renal nerves contribute to hypertension in Schlager BPH/2J mice.

Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J.

Circadian Differences in the Contribution of the Brain Renin-Angiotensin System in Genetically Hypertensive Mice.

Genetically hypertensive BPH/2J mice are recognized as a neurogenic model of hypertension, primarily based on sympathetic overactivity and greater neuronal activity in cardiovascular regulatory brain regions. Greater activity of the central renin angiotensin system (RAS) and reactive oxygen species (ROS) reportedly contribute to other models of hypertension. Importantly the peripheral RAS contributes to the hypertension in BPH/2J mice, predominantly during the dark period of the 24 h light cycle.

Positive allosteric modulation of GABAA receptors attenuates high blood pressure in Schlager hypertensive mice.

Objective: Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors.

Methods: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5 mg/kg per day), or its vehicle, for a period of 2 weeks.

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice.

BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice.

Central proopiomelanocortin but not neuropeptide Y mediates sympathoexcitation and hypertension in fat fed conscious rabbits.

Objective: High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension.

A role for the lateral parabrachial nucleus in cardiovascular function and fluid homeostasis.

The lateral parabrachial nucleus (LPBN) is located in an anatomical position that enables it to perform a critical role in relaying signals related to the regulation of fluid and electrolyte intake and cardiovascular function from the brainstem to the forebrain. Early neuroanatomical studies have described the topographic organization of blood pressure sensitive neurons and functional studies have demonstrated a major role for the LPBN in regulating cardiovascular function, including blood pressure, in response to hemorrhages, and hypovolemia. In addition, inactivation of the LPBN induces overdrinking of water in response to a range of dipsogenic treatments primarily, but not exclusively, those associated with endogenous centrally acting angiotensin II.

Central nervous system dysfunction in obesity-induced hypertension.

The activation of the sympathetic nervous system is a major mechanism underlying both human and experimental models of obesity-related hypertension. While insulin and the adipokine leptin have long been thought to contribute to obesity-related neurogenic mechanisms, the evidence is now very strong that they play a major role, shown particularly in animal studies using selective receptor antagonists. There is not just maintenance of leptin's sympatho-excitatory actions as previously suggested but considerable amplification particularly in renal sympathetic nervous activity.

Predictors of mean arterial pressure morning rate of rise and power function in subjects undergoing ambulatory blood pressure recording.

Background: We determined clinical predictors of the rate of rise (RoR) in blood pressure in the morning as well as a novel measure of the power of the BP surge (BP(power)) derived from ambulatory blood pressure recordings.

Methods: BP(power) and RoR were calculated from 409 ambulatory blood pressure (ABP) recordings from subjects attending a cardiovascular risk clinic. Anthropometric data, blood biochemistry, and history were recorded.

Major contribution of the medial amygdala to hypertension in BPH/2J genetically hypertensive mice.

BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response to stress and is the only region found to have greater Fos during the night and daytime in BPH/2J compared with BPN/3J mice. To determine the contribution of the MeAm to hypertension, the effect of neuronal ablation on blood pressure (BP) was assessed in BPH/2J (n=7) and normotensive BPN/3J mice (n=7).

Energy metabolism in BPH/2J genetically hypertensive mice.

Recent evidence indicates that genetic hypertension in BPH/2J mice is sympathetically mediated, but these mice also have lower body weight (BW) and elevated locomotor activity compared with BPN/3J normotensive mice, suggestive of metabolic abnormalities. The aim of the present study was to determine whether hypertension in BPH/2J mice is associated with metabolic differences. Whole-body metabolic and cardiovascular parameters were measured over 24 h by indirect calorimetry and radiotelemetry respectively, in conscious young (10-13 weeks) and older (22-23 weeks) BPH/2J, normotensive BPN/3J and C57Bl6 mice.

Actions of rilmenidine on neurogenic hypertension in BPH/2J genetically hypertensive mice.

Objective: BPH/2J hypertensive mice have an exaggerated sympathetic contribution to blood pressure (BP). Premotor sympathetic neurons within the rostroventrolateral medulla (RVLM) are a major source of sympathetic vasomotor tone and major site of action of the centrally acting sympatholytic agent, rilmenidine. The relative cardiovascular effect of rilmenidine in BPH/2J versus normotensive BPN/3J mice was used as an indicator of the involvement of the RVLM in the sympathetic contribution to hypertension in BPH/2J mice.

GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice.

Objective: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice.

Exposure to a high-fat diet during development alters leptin and ghrelin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits.

Exposure to maternal obesity or a maternal diet rich in fat during development may have adverse outcomes in offspring, such as the development of obesity and hypertension. The present study examined the effect of a maternal high-fat diet (m-HFD) on offspring blood pressure and renal sympathetic nerve activity, responses to stress, and sensitivity to central administration of leptin and ghrelin. Offspring of New Zealand white rabbits fed a 13% HFD were slightly heavier than offspring from mothers fed a 4% maternal normal fat diet (P<0.

A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice.

Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice.

Cardiovascular role of angiotensin type1A receptors in the nucleus of the solitary tract of mice.

Aims: The nucleus of the solitary tract (NTS) is important for cardiovascular regulation and contains angiotensin type 1A (AT1A) receptors. To assess its function, we examined the effect of expressing in AT1A receptors in the NTS of mice lacking these receptors.

Methods And Results: Bilateral microinjections of lentivirus expressing AT1A receptors (AT1Av mice, n = 6) or green fluorescent protein (GFPv, n = 8, control) under the control of the PRSx8 promotor were made into the NTS of AT1A receptors null mice (AT1A(-/-)).

Reduced preprandial dipping accounts for rapid elevation of blood pressure and renal sympathetic nerve activity in rabbits fed a high-fat diet.

Consumption of a high-fat diet (HFD) by rabbits results in increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) within 1 wk. Here, we determined how early this activation occurred and whether it was related to changes in cardiovascular and neural 24-h rhythms. Rabbits were meal-fed a HFD for 3 wks, then a normal-fat diet (NFD) for 1 wk.

Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is a heritable neurodegenerative disorder, with heart disease implicated as one major cause of death. While the responsible mechanism remains unknown, autonomic nervous system (ANS) dysfunction may play a role. We studied the cardiac phenotype in R6/1 transgenic mice at early (3 months old) and advanced (7 months old) stages of HD.

Angiotensin 1A receptors transfected into caudal ventrolateral medulla inhibit baroreflex gain and stress responses.

Aims: The caudal ventrolateral medulla (CVLM) is important for autonomic regulation and is rich in angiotensin II type 1A receptors (AT(1A)R). To determine their function, we examined whether the expression of AT(1A)R in the CVLM of mice lacking AT(1A)R (AT(1A)(-/-)) alters baroreflex sensitivity and cardiovascular responses to stress.

Methods And Results: Bilateral microinjections into the CVLM of AT(1A)(-/-) mice of lentivirus with the phox-2 selective promoter (PRSx8) were made to express either AT(1A)R (Lv-PRSx8-AT(1A)) or green fluorescent protein (Lv-PRSx8-GFP) as a control.

Angiotensin type 1A receptors in C1 neurons of the rostral ventrolateral medulla modulate the pressor response to aversive stress.

The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT(1A)Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT(1A)Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT(1A)R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT(1A)R promoter.

Renal sympathetic activation from long-term low-dose angiotensin II infusion in rabbits.

Objective: Activation of renal sympathetic nerve activity (RSNA) has not been observed during long-term infusion of angiotensin II (AngII) which results in marked hypertension, despite activation of hypothalamic autonomic regions. We examined whether the function of central pathways influencing sympathetic activity is altered in conscious rabbits given a low dose of AngII that produces a modest hypertension and, therefore, limited secondary complications.

Methods: Rabbits received AngII (20-30 ng/kg per min, subcutaneously) or sham treatment for 3 months at which time they were implanted with a renal sympathetic nerve electrode and the responses to airjet stress, baroreflexes and hypoxia were examined.

Renin-angiotensin and sympathetic nervous system contribution to high blood pressure in Schlager mice.

Objective: Schlager hypertensive (BPH/2J) mice have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS), but the contribution of the renin-angiotensin system (RAS) is unclear. In the present study, we examined the cardiovascular effects of chronically blocking the RAS in BPH/2J mice.

Methods: Schlager normotensive (BPN/3J, n = 6) and BPH/2J mice (n = 8) received the angiotensin AT 1A-receptor antagonist losartan (150 mg/kg per day) in drinking water for 2 weeks.

Genes influencing circadian differences in blood pressure in hypertensive mice.

Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP.

Global identification of the genes and pathways differentially expressed in hypothalamus in early and established neurogenic hypertension.

The hypothalamus has an important etiological role in the onset and maintenance of hypertension and stress responses in the Schlager high blood pressure (BP) (BPH/2J) mouse, a genetic model of neurogenic hypertension. Using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays we identified 1,019 hypothalamic genes whose expression differed between 6 wk old BPH/2J and normal BP (BPN/3J) strains, and 466 for 26 wk old mice.

Role of the medial amygdala in mediating responses to aversive stimuli leading to hypertension.

1. The amygdala is a part of the limbic system that is associated with mediating the emotional and hormonal response to stress and although studies have focused on the central amygdala, there is increasing evidence that the medial amygdala is a major region activated by stressful stimuli. 2.

Forebrain regions affected by lateral parabrachial nucleus serotonergic mechanisms that influence sodium appetite.

Blockade of serotonergic receptors in the lateral parabrachial nucleus (LPBN), via bilateral injections of nonselective 5-hydroxytryptamine (5-HT)(1/2)-receptor antagonist, methysergide causes a robust sodium appetite. Our aim was to elucidate which brain regions are activated when serotonergic pathways to the LPBN are blocked and combined with subcutaneous injection of isoproterenol causing a salt appetite. In the experimental group, conscious rats were administered methysergide (4 microg/0.