Importance of Awareness and Careful Follow-Up of Suspected IgG4-Related Periaortitis.

IgG4-related disease may cause large vessel vasculitis, which often affects males in their 60s. Here, we report a case of suspected IgG4-related periaortitis in a 76-year-old man with lower left-side chest pain and hypertension based on computed tomography findings of thickened lesions surrounding the abdominal aorta and mesenteric arteries after ruling out acute cardiovascular diseases. His serum IgG4 levels were high, but the C-reactive protein and D-dimer levels were within normal limits. Because IgG4-related periaortitis was suspected, the patient was carefully monitored for blood pressure control, inflammatory markers, and renal function. Steroid therapy was not initiated, however, due to the difficulties performing a biopsy targeting periaortitis to obtain a definitive diagnosis and possible severe complications. During follow-up observation, IgG4-related kidney disease was suspected based on a slight increase in the serum creatinine levels and a renal biopsy was considered. Just before performing the renal biopsy, we observed left renal hydronephrosis caused by spreading retroperitoneal fibrosis. Immediate ureteral stent implantation and initiation of steroid therapy successfully improved the renal function and decreased the serum IgG4 level, respectively. Although relatively rare, IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis should be considered in the differential diagnosis of aortic diseases, even after ruling out serious major acute cardiovascular diseases. Cardiologists should also be aware of the possible progression and systemic spread of this disease.

A Retrospective Analysis of Risk Factors for Mortality during Hemodialysis at a General Hospital That Treats Comprehensive Diseases.

Objective We analyzed adverse events retrospectively during a three-year follow-up of patients undergoing hemodialysis at the dialysis center of our general hospital that can treat comprehensive diseases and conducted an exploratory study focusing on the risk factors that determine the prognosis of hemodialysis patients. Methods A total of 132 hemodialysis patients at our dialysis center as of June 2017 were included in the study. Data on event incidence, including death and various clinical indicators, were collected in the electronic medical record for three years until June 2020. Results Between June 2017 and June 2020, 33 of the 132 patients died. The mortality group had a lower body mass index (BMI) and a longer duration of hemodialysis already carried out with more preexisting upper gastrointestinal (GI) bleeding, infections, ischemic heart disease (IHD), and malignancy than the survival group. Furthermore, the mortality group took more warfarin, aspirin, proton pump inhibitors and less H2 blockers than the survival group. Occurrence of upper or lower GI bleeding was similar between the mortality and survival groups. In a univariate analysis for mortality, the odds ratio was significantly higher for a low BMI (<18), long duration of hemodialysis, history of upper GI bleeding, and presence of IHD. Multivariable-adjusted odds ratios for mortality were significantly higher for cases with a history of upper GI bleeding and BMI <18. Conclusion A history of upper GI bleeding and low BMI may be poor prognostic factors of hemodialysis patients. Careful management of upper GI bleeding and a low BMI are required during the initiation of hemodialysis.

Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation.

Hypertension is associated with systemic inflammation. The activation of the sympathetic nervous system is critically involved in the pathogenesis of hypertension. Brain perivascular macrophages (PVMs) can be affected by circulating inflammatory cytokines, and the contribution of brain PVMs to sympathoexcitation has been demonstrated in a heart failure model. We thus investigated whether brain PVMs contribute to the development of hypertension through sympathoexcitation. Stroke-prone spontaneously hypertensive rats (SHRSP) developed hypertension over an 8-week period from 4 to 12 weeks of age. The number of brain PVMs and plasma interleukin-1ß levels significantly increased at the ages of 8 and 12 weeks in SHRSP compared with normotensive Wistar-Kyoto rats (WKY). To determine the contribution of brain PVMs to blood pressure elevation, we intracerebroventricularly injected liposome-encapsulated clodronate, which eliminates macrophages by inducing apoptosis, into 8-week-old rats; we then assessed its effects in 10-week-old rats. Clodronate treatment attenuated the increase in mean blood pressure in SHRSP but not in WKY. Clodronate treatment reduced the depressor effect of hexamethonium, an index of sympathetic activity; it also reduced neuronal activity in sympathetic regulatory nuclei such as the hypothalamic paraventricular nucleus and rostral ventrolateral medulla and reduced the expression of cyclooxygenase-2 and prostaglandin E2, a downstream pathway in activated macrophages, in SHRSP but not in WKY. Furthermore, clodronate treatment attenuated the increase in blood pressure and renal sympathetic nerve activity in response to an acute intravenous injection of interleukin-1ß in WKY. In conclusion, brain PVMs contribute to the development of hypertension via sympathetic activation. PVMs may be activated by increased levels of circulating interleukin-1ß.

Hypoxia-inducible factor-1 α deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension.

Hypoxemia is seen in patients with pulmonary hypertension and hypoxic pulmonary vasoconstriction worsens their clinical condition. However, vasoconstriction is not the only aspect through which hypoxia induces the progression to pulmonary hypertension. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor responding to hypoxic conditions by regulating hundreds of genes involved in angiogenesis, erythropoiesis, inflammation, and proliferation. We sought to determine the contribution of HIF-1α in myeloid lineage cells to the pulmonary vascular response to chronic exposure to hypoxia. We generated myeloid-specific HIF-1α knockout (MyeHIF1KO) mice by using Cre-lox P system, and exposed them to hypoxic conditions for 3 weeks to induce pulmonary hypertension. Macrophages from MyeHIF1KO and control mice were used for western blotting, RT-qPCR, chemotaxis assay, and ATP assay. MyeHIF1KO mice exposed to hypoxia for 3 weeks exhibited a significant reduction in the right ventricular systolic pressure accompanied by a decrease in the ratio of the right ventricular weight to left ventricular weight, muscularization of the small pulmonary arteries, and infiltration of macrophages into the lung and right ventricle compared with control mice. HIF-1α-deficient peritoneal macrophages showed less migration toward monocyte chemoattractant protein-1 and a decrease in intracellular ATP levels. These results indicate that HIF-1α in macrophages contributes to the progression of pulmonary vascular remodeling and pulmonary hypertension induced by chronic exposure to hypoxic conditions. The inhibition of myeloid-specific HIF-1α may be a novel therapeutic strategy for the treatment of pulmonary hypertension.

Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease.

OBJECTIVE: Sympathoexcitation plays an important role in the pathogenesis of hypertension in patients with chronic kidney disease (CKD). The paraventricular nucleus of the hypothalamus (PVN) in the brain controls sympathetic outflow through γ-amino butyric acid (GABA)-ergic mechanisms. Renal denervation (RDN) exerts a long-term antihypertensive effect in hypertension with CKD; however, the effects of RDN on sympathetic nerve activity and GABA-ergic modulation in the PVN are not clear. We aimed to elucidate whether RDN modulates sympathetic outflow through GABA-ergic mechanisms in the PVN in hypertensive mice with CKD. METHODS AND RESULTS: In 5/6-nephrectomized male Institute of Cancer Research mice (Nx) at 4 weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by sympathoexcitation. The Nx-mice underwent RDN or sham operation, and the mice were divided into three groups (Control, Nx-Sham, and Nx-RDN). At 2 weeks after RDN, SBP was significantly decreased and urinary sodium excretion was increased in Nx-RDN compared with Nx-Sham. Urinary norepinephrine excretion (uNE) levels did not differ significantly between Nx-RDN and Nx-Sham. At 6 weeks after RDN, SBP continued to decrease and uNE levels also decreased in Nx-RDN compared with Nx-Sham. Bicuculline microinjection into the PVN increased mean arterial pressure and lumbar sympathetic nerve activity in all groups. The pressor responses and change in lumbar sympathetic nerve activity were significantly attenuated in Nx-Sham, but were enhanced in Nx-RDN at 6 weeks after RDN. CONCLUSIONS: The findings from the present study indicate that RDN has a prolonged antihypertensive effect and, at least in the late phase, decreases sympathetic nerve activity in association with enhanced GABA-ergic input into the PVN in mice with CKD.

Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension.

AIMS: An important pathogenic mechanism in the development of idiopathic pulmonary arterial hypertension is hypothesized to be a cancer-like cellular proliferation independent of haemodynamics. However, because the vascular lesions are inseparably coupled with haemodynamic stress, the fate of the lesions is unknown when haemodynamic stress is eliminated. METHODS AND RESULTS: We applied left pulmonary artery banding to a rat model with advanced pulmonary hypertension to investigate the effects of decreased haemodynamic stress on occlusive vascular lesions. Rats were given an injection of the VEGF blocker Sugen5416 and exposed to 3 weeks of hypoxia plus an additional 7 weeks of normoxia (total 10 weeks) (SU/Hx/Nx rats). The banding surgery to reduce haemodynamic stress to the left lung was done at 1 week prior to (preventive) or 5 weeks after (reversal) the SU5416 injection. All SU/Hx/Nx-exposed rats developed severe pulmonary hypertension and right ventricular hypertrophy. Histological analyses showed that the non-banded right lungs developed occlusive lesions including plexiform lesions with marked perivascular cell accumulation. In contrast, banding the left pulmonary artery not only prevented the development of but also reversed the established occlusive lesions as well as perivascular inflammation in the left lungs. CONCLUSION: Our results indicate that haemodynamic stress is prerequisite to the development and progression of occlusive neointimal lesions in this rat model of severe pulmonary hypertension. We conclude that perivascular inflammation and occlusive neointimal arteriopathy are driven by haemodynamic stress.

Japanese soybean paste miso lessens sympathovagal imbalance and attenuates brain sodium sensitivity in mice with pressure overload.

Miso is a traditional Japanese food that is made from fermented soybeans, and it can attenuate salt-induced hypertension in salt-sensitive hypertensive rats. We also recently demonstrated that regular miso intake inhibits salt-sensitive sympathoexcitation in mice with pressure overload (CPO). In this context, sympathoexcitation contributes to the pathogenesis of hypertension, including salt-sensitive hypertension. Therefore, we hypothesized that miso might be able to improve sympathovagal imbalance, thereby attenuating salt-induced hypertension. We first treated mice with an intraperitoneal (IP) injection of miso supernatant that was suspended in a 0.28 M sodium solution. Five hours after the miso injection, the mice's systolic blood pressure and heart rate had decreased, with a lower ratio of low frequency (LF) to high frequency (HF) power of heart rate variability. However, an IP injection of high-sodium saline solution (0.28 M sodium) alone had no effects on these parameters. To evaluate the effects of miso on sodium sensitivity in CPO-mice, we also performed aortic banding. At 4 weeks after the surgery, the mice received an IP injection of miso supernatant or high-sodium saline. The ratio of LF/HF increased after the high-sodium saline injection, although not after the miso injection, which indicated that miso inhibited the enhanced sodium sensitivity for sympathetic activity in CPO-mice. We also pre-treated CPO-mice with an intracerebroventricular infusion of miso supernatant to evaluate its effect on increased cerebrospinal fluid (CSF) sodium-induced hypertension. Diluted miso supernatant (in a 0.14 M sodium solution) attenuated the increased CSF sodium-induced hypertension, although pre-treatment with normal-sodium (0.14 M) saline failed to change the hypertension. These results suggest that miso acts on the brain to sway the sympathovagal balance towards a parasympathetic nerve dominant state, and to attenuate the brain sodium sensitivity for sympathoexcitation in CPO-mice.

Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation.

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

Novel dual endothelin receptor antagonist macitentan reverses severe pulmonary arterial hypertension in rats.

The efficacy of endothelin (ET) receptor antagonist bosentan in patients with severe pulmonary arterial hypertension (PAH) remains limited, partly because its higher doses for potential blockade of ET receptors have never been tested due to liver dysfunction. We hypothesized that rigorous blockade of ET receptors using the novel dual ET receptor antagonist macitentan would be effective in treating severe PAH without major side effects in a preclinical model appropriately representing the human disorder. In normal rats, 30 mg·kg·d of macitentan completely abolished big ET-1-induced increases in right ventricle (RV) systolic pressure. Adult male rats were injected with SU5416, a vascular endothelial growth factor blocker, and exposed to hypoxia for 3 weeks and then to normoxia for an additional 5 weeks (total 8 weeks). In intrapulmonary arterial rings isolated from rats with severe PAH, macitentan concentration dependently inhibited ET-1-induced contraction. Long-term treatment with macitentan (30 mg·kg·d, from week 3 to 8) reversed the high RV systolic pressure with preserved cardiac output. Development of RV hypertrophy, luminal occlusive lesions and medial wall thickening were also significantly improved without increasing serum levels of liver enzymes by macitentan. In conclusion, efficacious blockade of ET receptors with macitentan would reverse severe PAH without major adverse effects.

Miso (Japanese soybean paste) soup attenuates salt-induced sympathoexcitation and left ventricular dysfunction in mice with chronic pressure overload.

The hypothalamic mineralocorticoid receptor (MR)-angiotensin II type 1 receptor (AT1R) pathway is activated in mice with chronic pressure overload (CPO). When this activation is combined with high salt intake, it leads to sympathoexcitation, hypertension, and left ventricular (LV) dysfunction. Salt intake is thus an important factor that contributes to heart failure. Miso, a traditional Japanese food made from fermented soybeans, rice, wheat, or oats, can attenuate salt-induced hypertension in rats. However, its effects on CPO mice with salt-induced sympathoexcitation and LV dysfunction are unclear. Here, we investigated whether miso has protective effects in these mice. We also evaluated mechanisms associated with the hypothalamic MR-AT1R pathway. Aortic banding was used to produce CPO, and a sham operation was performed for controls. At 2 weeks after surgery, the mice were given water containing high NaCl levels (0.5%, 1.0%, and 1.5%) for 4 weeks. The high salt loading in CPO mice increased excretion of urinary norepinephrine (uNE), a marker of sympathetic activity, in an NaCl concentration-dependent manner; however, this was not observed in Sham mice. Subsequently, CPO mice were administered 1.0% NaCl water (CPO-H) or miso soup (1.0% NaCl equivalent, CPO-miso). The expression of hypothalamic MR, serum glucocorticoid-induced kinase-1 (SGK-1), and AT1R was higher in the CPO-H mice than in the Sham mice; however, the expression of these proteins was attenuated in the CPO-miso group. Although the CPO-miso mice had higher sodium intake, salt-induced sympathoexcitation was lower in these mice than in the CPO-H group. Our findings indicate that regular intake of miso soup attenuates salt-induced sympathoexcitation in CPO mice via inhibition of the hypothalamic MR-AT1R pathway.

Central neuregulin-1/ErbB signaling modulates cardiac function via sympathetic activity in pressure overload-induced heart failure.

OBJECTIVES: Neuregulin-1 (NRG-1)/ErbB signaling in the heart is reported to have a crucial role in heart failure. We recently demonstrated that NRG-1 signaling has sympathoinhibitory effects in the brain cardiovascular control center. How this central signaling impacts sympathoexcitation in heart failure, however, is unknown. Here we examined the role of central NRG-1/ErbB signaling in modulating the sympathetic nervous system in pressure overload-induced heart failure. METHODS AND RESULTS: Pressure overload-induced heart failure was induced in Wistar-Kyoto rats by banding the abdominal aorta. Rats were followed up for 15 weeks. Compared to sham-operated rats, aortic-banded rats showed left ventricle (LV) hypertrophy, LV dilation, and LV dysfunction [reducing fractional shortening (%fractional shortening), increased LV end-diastolic pressure, decreased positive and negative pressure differential (±dp/dt(max))], and increased urinary norepinephrine excretion. Aortic banding led to reduced expression of NRG-1 in the brainstem at 10 weeks after banding and reduced expression of ErbB2 at 5 weeks, but did not affect ErbB4. Central administration of recombinant NRG-1ß at 5 weeks for 2 weeks attenuated LV hypertrophy, improved LV dilatation, prevented LV dysfunction (improvement of %fractional shortening and ±dp/dt(max), and reduction of LV end-diastolic pressure), and lowered urinary norepinephrine excretion at 10 weeks, and these effects were still observed at 15 weeks. CONCLUSION: NRG-1/ErbB signaling in the brainstem is impaired during the progression of pressure overload-induced heart failure. Activation of central NRG-1 signaling improves cardiac function through sympathoinhibition. These findings provide a new treatment concept and support the benefit of NRG-1 treatment in heart failure.

Blood pressure variability activates cardiac mineralocorticoid receptor and induces cardiac remodeling in hypertensive rats.

BACKGROUND: Hypertensive patients with large blood pressure variability (BPV) have aggravated target organ damage. Because the aldosterone/mineralocorticoid receptor (MR) system is a possible mechanism of hypertensive organ damage, we investigated in spontaneously hypertensive rats (SHRs) whether a specific MR blocker, eplerenone, would prevent BPV-induced aggravation of hypertensive cardiac remodeling. METHODS AND RESULTS: A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHRs. SAD increased BPV without changing mean BP. SAD induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac hypertrophy, resulting in LV systolic dysfunction. Immunohistostaining revealed SAD-induced translocation of MRs into the nuclei (ie, MR activation) of the intramyocardial arterial medial cells and cardiac myocytes. SAD increased phosphorylation of p21-activated kinase1 (PAK1), a regulator of MR nuclear translocation. Chronic administration of a subdepressor dose of eplerenone prevented MR translocation, macrophage infiltration, myocardial fibrosis, cardiac hypertrophy, and LV dysfunction, while not affecting BPV. Circulating levels of aldosterone and cortisol were not changed by SAD. CONCLUSIONS: Eplerenone inhibited the aggravation of cardiac inflammation and hypertensive cardiac remodeling, and thereby prevented progression of LV dysfunction in SHRs with large BPV. This suggests that the PAK1-MR pathway plays a role in cardiac inflammation and remodeling induced by large BPV superimposed on hypertension, independent of circulating aldosterone.

Role of hypothalamic angiotensin type 1 receptors in pressure overload-induced mineralocorticoid receptor activation and salt-induced sympathoexcitation.

Pressure overload enhances salt-induced sympathoexcitation through hypothalamic mineralocorticoid receptor (MR)-epithelial Na channel activation. Pressure overload also increases hypothalamic angiotensin type 1 receptors (AT1R). However, the role of AT1R in pressure overload-induced MR activation and salt-induced sympathoexcitation remains unknown. Therefore, the aim of the present study was to address this question. We performed aortic banding (AB) on mice from the Institute of Cancer Research. The expression of hypothalamic MR, serum/glucocorticoid-induced protein kinase-1 (SGK-1) and AT1R increased independently of plasma renin activity at 2 or 4 weeks after AB. Next, we performed AB in AT1aR-knockout (KO) mice and c57BL6/J wild-type (WT) mice. Sham-operated (Sham) mice were used as a control. Four weeks after AB (AB-KO or AB-WT), the expression of hypothalamic MR and SGK-1 increased in both AB-WT and AB-KO compared with Sham-WT and Sham-KO, respectively. The expression of AT1R was also greater in AB-WT than in Sham-WT. In addition, mice were fed a high-salt (8%) diet for an additional 4 weeks (ABH-KO and ABH-WT). High salt loading increased the urinary excretion of norepinephrine, a marker of sympathetic activity in ABH-WT, concomitant with hypothalamic MR activation, but not in ABH-KO. These results indicate that pressure overload activated hypothalamic MR independently of AT1R. After salt intake, however, AT1R was necessary to maintain hypothalamic MR activation and salt-induced sympathoexcitation.

Inhibition of neuregulin-1/ErbB signaling in the rostral ventrolateral medulla leads to hypertension through reduced nitric oxide synthesis.

BACKGROUND: We recently reported that activation of neuregulin-1 (NRG-1)/ErbB signaling in the rostral ventrolateral medulla (RVLM) of the brainstem elicits sympathoinhibition and depressor effects, and ErbB2-type ErbB receptors are involved in the neurogenic mechanisms of hypertension. Nitric oxide (NO) in the RVLM also elicits sympathoinhibition and depressor effects. NRG-1 enhances NO synthase (NOS) expression in several tissues. Here, we tested the hypothesis that ErbB2 inhibition in the RVLM contributes to increasing blood pressure via modulating the effects of NOS. METHODS: We measured the effects of chronic intracisternal infusion of an ErbB2 antagonist and local ErbB2 inhibition in the RVLM using RNA interference (ErbB2 siRNA) on blood pressure (BP), heart rate (HR), norepinephrine excretion (uNE), and NOS expression in the RVLM. The central effects of the ErbB2 antagonist or NRG-1ß were investigated with or without chronic and acute prior administration of a NOS inhibitor. RESULTS: Intracisternal infusion of the ErbB2 antagonist and ErbB2 siRNA increased BP, HR, and uNE; and reduced neuronal and endothelial NOS expression in the RVLM. Further, prior systemic administration of a NOS inhibitor abolished the pressor response to intracisternal infusion of an ErbB2 antagonist in awake rats. Prior injection of a NOS inhibitor or γ-aminobutyric acid-A receptor antagonist into the RVLM attenuated the depressor response to NRG-1 in anesthetized rats. CONCLUSIONS: These findings indicate that inhibition of ErbB2 expression in the RVLM leads to hypertension, at least in part, by reducing NO synthesis and inhibiting γ-aminobutyric acid activity. NRG-1/ErbB signaling in the RVLM might exist upstream of NO synthesis.

Inhibition of oxidative stress in rostral ventrolateral medulla improves impaired baroreflex sensitivity in stroke-prone spontaneously hypertensive rats.

Reactive oxygen species (ROS) in rostral ventrolateral medulla (RVLM) of brainstem contribute to sympathoexcitation and are critically involved in the pathogenesis of hypertension. Baroreflex sensitivity (BRS) is a valuable prognostic parameter of the autonomic nervous system, and is impaired in hypertension. The aim of the present study was to determine whether or not a chronic reduction of ROS in the RVLM improves impaired BRS in hypertensive rats. We transfected adenovirus vectors encoding either manganese superoxide dismutase (AdMnSOD) or ß-galactosidase (AdLacZ) into the RVLM of stroke-prone spontaneously hypertensive rats (SHRSP). We measured BRS using the spontaneous sequence method. BRS was significantly lower in SHRSPs than in Wistar-Kyoto rats. In the AdMnSOD-transfected SHRSP, blood pressure, heart rate, and sympathetic nervous system activation were significantly decreased from day 5 after the gene transfer. BRS in the AdMnSOD-transfected SHRSP was significantly increased from day 4 after the gene transfer with the reduction of ROS in the RVLM. Furthermore, in the AdMnSOD-transfected SHRSP, intravenous infusion of atropine dramatically decreased BRS. In contrast, in the AdLacZ-transfected SHRSP, atropine did not decrease BRS. These results suggest that chronic reduction of ROS in the local RVLM improves the impaired BRS in SHRSP through inhibition of the sympathetic component.

Different role of oxidative stress in paraventricular nucleus and rostral ventrolateral medulla in cardiovascular regulation in awake spontaneously hypertensive rats.

OBJECTIVE: The rostral ventrolateral medulla (RVLM) of the brainstem and the paraventricular nucleus of the hypothalamus (PVN) are involved in the neural mechanisms of hypertension. Oxidative stress in the RVLM contributes to the enhanced central sympathetic outflow that leads to hypertension in experimental models of hypertension, such as spontaneously hypertensive rats (SHRs). We investigated the relative contribution of oxidative stress in the PVN and RVLM of SHR in blood pressure (BP) regulation. METHODS AND RESULTS: We transfected adenovirus vectors encoding the manganese superoxide dismutase gene (AdMnSOD) or ß-galactosidase gene (AdLacZ) bilaterally into the RVLM or PVN. Mean arterial pressure (MAP) and heart rate (HR) were monitored using a radiotelemetry system. Oxidative stress levels in the PVN of SHR evaluated by thiobarbituric acid-reactive substances were enhanced compared with those of Wistar-Kyoto rats and reduced by MnSOD transfection compared with nontransfected SHR. MAP and HR of AdMnSOD-RVLM-transfected SHR were decreased compared with AdLacZ-RVLM-transfected SHR. In contrast, MAP of AdMnSOD-PVN-transfected SHR was not decreased compared with AdLacZ-PVN-transfected SHR, but HR was decreased compared with AdLacZ-PVN-transfected SHR. MnSOD transfection into both the RVLM and PVN of SHR decreased MAP and elicited a profound decrease in HR. CONCLUSION: These findings indicate that inhibition of oxidative stress in the PVN decreases HR, but not BP in SHR, and elicits a further decrease in HR, but not BP, by interacting with the RVLM. Taken together, the oxidative stress in the PVN and RVLM plays a different role for cardiovascular regulation in SHR.

Decreased brain sigma-1 receptor contributes to the relationship between heart failure and depression.

AIMS: Depression often coexists with cardiovascular disease, such as hypertension and heart failure, in which sympathetic hyperactivation is critically involved. Reduction in the brain sigma-1 receptor (S1R) functions in depression pathogenesis via neuronal activity modulation. We hypothesized that reduced brain S1R exacerbates heart failure, especially with pressure overload via sympathetic hyperactivation and worsening depression. METHODS AND RESULTS: Male Institute of Cancer Research mice were treated with aortic banding and, 4 weeks thereafter, fed a high-salt diet for an additional 4 weeks to accelerate cardiac dysfunction (AB-H). Compared with sham-operated controls (Sham), AB-H showed augmented sympathetic activity, decreased per cent fractional shortening, increased left ventricular dimensions, and significantly lower brain S1R expression. Intracerebroventricular (ICV) infusion of S1R agonist PRE084 increased brain S1R expression, lowered sympathetic activity, and improved cardiac function in AB-H. ICV infusion of S1R antagonist BD1063 increased sympathetic activity and decreased cardiac function in Sham. Tail suspension test was used to evaluate the index of depression-like behaviour, with immobility time and strain amplitude recorded as markers of struggle activity using a force transducer. Immobility time increased and strain amplitude decreased in AB-H compared with Sham, and these changes were attenuated by ICV infusion of PRE084. CONCLUSION: These results indicate that decreased brain S1R contributes to the relationship between heart failure and depression in a mouse model of pressure overload.

Oxidative stress in the rostral ventrolateral medulla modulates excitatory and inhibitory inputs in spontaneously hypertensive rats.

OBJECTIVES: The rostral ventrolateral medulla (RVLM) of the brainstem and the paraventricular nucleus (PVN) of the hypothalamus play crucial roles in central cardiovascular regulation. In hypertensive rats, an imbalance of excitatory and inhibitory inputs to the RVLM enhances central sympathetic outflow. Increased reactive oxygen species (ROS) in the RVLM also contribute to sympathoexcitation, leading to hypertension. The aim of the present study was to elucidate whether ROS in the RVLM modulate synaptic transmission via excitatory and inhibitory amino acids and influence the excitatory inputs to the RVLM from the PVN in spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: We transfected adenovirus vectors encoding the manganese superoxide dismutase (AdMnSOD) gene to scavenge ROS in the RVLM both in Wistar-Kyoto rats and SHRs. The decreases in blood pressure and renal sympathetic nerve activity (RSNA) evoked by injecting kynurenic acid, a glutamate receptor blocker, into the RVLM were attenuated, and the increases in blood pressure and RSNA evoked by injecting bicuculline, a γ-amino butyric acid (GABA) receptor blocker, into the RVLM were enhanced in AdMnSOD-transfected SHRs compared with adenovirus vectors encoding the ß-galactosidase (AdLacZ) gene-transfected SHRs. Furthermore, the increases in blood pressure and RSNA evoked by injecting bicuculline into the PVN were attenuated in AdMnSOD-transfected SHRs compared with AdLacZ-transfected SHRs. CONCLUSION: These findings suggest that ROS in the RVLM enhance glutamatergic excitatory inputs and attenuate GABAergic inhibitory inputs to the RVLM, thereby increasing sympathoexcitatory input to the RVLM from the PVN in SHRs.

Brain AT1 receptor activates the sympathetic nervous system through toll-like receptor 4 in mice with heart failure.

The activation of angiotensin II type 1 receptor (AT1R) in the brain plays a pivotal role in enhanced sympathetic drive in heart failure (HF). Activation of the AT1R in the brain produces oxidative stress and inflammation. Toll-like receptor 4 (TLR4) signaling in the brain induces the inflammatory cascade. We hypothesized that sympathoexcitation is mediated by the AT1R-activated TLR4 in the brainstem in HF. As a model of HF, the left coronary artery was ligated to induce a large myocardial infarction and subsequent chronic heart failure (CHF) in Institute of Cancer Research mice. On day 10 after the surgery, we started intracerebroventricular infusion of losartan (CHF-Los) or vehicle (CHF-Veh) via osmotic minipumps for 14 days. Expression level of the TLR4 in the brainstem was significantly higher in HF mice than in sham mice and significantly lower in CHF-Los mice than in CHF-Veh mice. Urinary norepinephrine excretion was significantly higher in HF mice than in sham mice and was significantly lower in CHF-Los than in CHF-Veh. Chronic intracerebroventricular infusion of angiotensin II increased the expression level of the second messenger of the TLR4. These results suggest that activation of the TLR4 via AT1R in the brainstem contributes to the sympathoexcitation probably due to the inflammation in the brain of the myocardial infarction-induced HF.