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BACKGROUND Atrial fibrillation (AF) is a common arrhythmia in the elderly, and causes complications such as cardioembolic stroke. Serum high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, has been reported to be a risk factor for developing AF in Western countries. However, few community-based studies have examined this issue in general Asian populations.Methods and Results:A total of 2,510 community-dwelling Japanese participants aged ≥40 years without a history of AF were divided into 4 groups according to the sex-specific quartiles of serum hs-CRP concentrations (Q1, lowest and Q4, highest) and followed up for 24 years. The hazard ratios and their 95% confidence intervals for the development of AF were estimated using a Cox proportional hazards model. During the follow up, 234 subjects developed AF. The risk of AF increased significantly with elevating serum hs-CRP levels after adjustment for potential confounding factors (hazard ratio [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.26 [0.83-1.92]; Q3, 1.77 [1.18-2.66]; and Q4, 1.89 [1.24-2.86]; P for trend

Type 2 Diabetes mellitus (T2DM) is one of the most common diseases in the world and its prevalence ratio is still increasing. Patients with T2DM have diverse pathophysiological changes like as macrovascular, microvascular diseases, cancers as well as abnormal glucose metabolism. Thus, there are urgent needs to develop relevant biomarkers for the broad range of pathophysiology in patients with T2DM. We analyzed the signatures of serum miRNAs with the miRNA array analysis and reverse-transcription based quantitative polymerase chain reaction (RT-qPCR) in 50 patients with type 2 DM (T2DM) and 15 normal subjects. Array analysis showed that 19 miRNAs were up-regulated more than 2-fold and 71 miRNAs were down-regulated less than 0.5 in T2DM in comparison with normal subjects. Top 5 of up-regulated miRNAs were miR-3619-3p, miR-557, miR-6850-5p, miR-3648, miR-4730, and 5 of most down-regulated miRNAs were miR-5100, miR-4454, miR-1260b, miR-7975, miR-6131. We selected 4 miRNAs for validation analysis with RT-qPCR based on the abundance enough for reliable analyses and disease-specificities reported in previous reports. Serum miR-126-3p was down-regulated (3.21-fold, p

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 H

A 75-year-old woman with no significant medical history was admitted to our hospital with congestive heart failure. Echocardiography revealed left ventricle (LV) systolic dysfunction [LV ejection fraction (LVEF) 18%] and diffuse LV hypokinesis mimicking dilated cardiomyopathy. Her brain natriuretic peptide (BNP) level was elevated (1214.3 pg/mL). Standard medications for heart failure failed to ameliorate her cardiac failure symptoms. Echocardiography on admission revealed thickening of the basal interventricular septum without morphological changes. Cardiac magnetic resonance imaging showed late enhancement in the epicardial side dominance of the LV at the late phase. Lysozyme and soluble interleukin 2 receptor levels were elevated. No abnormalities were found in the lungs, eyes, or skin, and she was diagnosed with cardiac sarcoidosis. At 23 days after beginning treatment, the patient received oral steroid therapy (prednisolone 30 mg/day) along with standard heart failure medications. The dose was tapered by 5 mg at 4-week intervals and then maintained at 10 mg per day. At 17 days after initiating steroid therapy, her BNP value decreased and remained at a low level. Echocardiography showed improvement of the LV dimensions and LVEF. In patients with severe LV dysfunction diagnosed with cardiac sarcoidosis, we propose that careful steroid therapy be considered, even for elderly patients.

Aims Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary vascular resistance (PVR). Thrombotic lesions are common pathological findings. The pulmonary artery has a unique property regarding the vasoconstrictive response to thrombin, which is mediated by proteinase-activated receptor 1 (PAR1). We aim to elucidate the role of PAR1 in the development and progression of PH. Methods and results A rat model of monocrotaline-induced PH and a mouse model of hypoxia (Hx)-induced PH were used to investigate the effects of atopaxar (a PAR1 antagonist) and PAR1 knockout on haemodynamic parameters, right ventricular hypertrophy (RVH), vascular remodelling and survival. In perfused lung preparations, the pressor response to PAR1 agonist was significantly augmented in monocrotaline-induced PH. Both the preventive and therapeutic administration of atopaxar significantly inhibited the increase in PVR and the development of RVH and prolonged survival. A real-time PCR revealed that the level of PAR1 mRNA in the pulmonary artery was significantly higher than that in any of the systemic arteries examined in control rats, and the level was significantly up-regulated in monocrotaline-induced PH. PAR1 gene knockout significantly attenuated the haemodynamic and histological findings in the mouse model of Hx-induced PH. Conclusion The specific expression of PAR1 in the pulmonary artery and its up-regulation were suggested to play a critical role in the development and progression of experimental PH in murine models. PAR1 is a potential therapeutic target for the treatment of PH.

It is not established whether central blood pressure (BP) evaluated by a radial pulse wave analysis is useful to predict cardiovascular prognoses. We tested the hypothesis that central BP predicts future cardiovascular events in treated hypertensive subjects. We conducted a multicenter, observational cohort study of 3566 hypertensives being treated with antihypertensive medications at 27 institutions in Japan. We performed the radial pulse wave analyses using applanation tonometry in all subjects. The primary outcome was the incidence of any of the following: stroke, myocardial infarction (MI), sudden cardiac death, and acute aortic dissection. The mean age of the subjects was 66.0 ± 10.9 years, and 50.6% were male. The mean brachial SBP and central SBP were 138 ± 18 mm Hg and 128 ± 19 mm Hg, respectively. When the central SBP was divided into quintiles, the number of events was least in the 2nd quintile, and we set it as the reference. In the Cox regression analysis adjusting for age, sex, body mass index, creatinine, diabetes, use of β-blocker, and history of MI/stroke, the patients in the 3rd (hazard ratio (HR) 3.55, 95% confidence interval 1.29-9.78, p = 0.014), 4th (HR 4.12, 95% CI 1.53-11.10, p = 0.005), and 5th quintiles (HR 2.87, 95% CI 1.01-8.18, p = 0.048) had a significantly higher incidence of cardiovascular events compared to the 2nd quintile. The results were essentially unchanged when brachial DBP was additionally adjusted. In conclusion, in treated hypertensives, high central SBP was associated with worse cardiovascular outcomes.

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.

The sympathetic nervous system plays a critical role in the pathogenesis of hypertension. The central nervous system (CNS) organizes the sympathetic outflow and various inputs from the periphery. The brain renin–angiotensin system has been studied in various regions involved in controlling sympathetic outflow. Recent progress in cardiovascular research, particularly in vascular biology and neuroscience, as well as in traditional physiological approaches, has advanced the field of the neural control of hypertension in which the CNS plays a vital role. Cardiovascular research relating to hypertension has focused on the roles of nitric oxide, oxidative stress, inflammation, and immunity, and the network among various organs, including the heart, kidney, spleen, gut, and vasculature. The CNS mechanisms are similarly networked with these factors and are widely studied in neuroscience. In this review, I describe the development of the conceptual flow of this network in the field of hypertension on the basis of several important original research articles and discuss potential future breakthroughs leading to clinical precision medicine.

Women with a history of preeclampsia exhibit increased salt sensitivity of blood pressure at postpartum, which might be responsible for their increased risk of future cardiovascular diseases. However, it is unclear whether preeclampsia can cause increased salt sensitivity at postpartum. Vasopressin may play a role in the pathogenesis of preeclampsia and salt-sensitive hypertension. Therefore, the aim of this study was to determine whether the exposure to preeclampsia, as elicited by placental ischemia, causes increased salt sensitivity at postpartum, and if so, whether vasopressin is involved in its process.We used a reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. Pregnant Sprague-Dawley rats were categorized into the following two groups: RUPP-operated and sham-operated (SHAM) control groups. A 1-week-long high-salt diet was initiated at 3 weeks postpartum. The high-salt diet-induced increase in mean arterial pressure was significantly greater in the RUPP group than in the SHAM group. In addition, the plasma levels of copeptin, a substitute for plasma vasopressin, increased and serum osmolality decreased in the RUPP group. Double immunostaining revealed that the expression of c-Fos, a marker of neural activity, in vasopressin-producing neurons and presympathetic neurons in the hypothalamic paraventricular nucleus was significantly elevated in the RUPP group. The oral administration of conivaptan, the dual V1a/V2 vasopressin receptor antagonist, during high-salt diet abolished the enhanced increase in mean arterial pressure in RUPP rats.Prior exposure to placental ischemia causes increased salt sensitivity of blood pressure at postpartum probably due to enhanced vasopressin production and secretion.

Background Inflammation within paraventricular nucleus of the hypothalamus (PVN), a key circulatory control center in the hypothalamus, is an important pathology of sympathetic hyperactivity. Brain inflammation is mainly mediated by microglia, innate immune cells in the brain. Activated microglia produce inflammatory cytokines with alteration of their morphology. Increase in inflammatory cytokines synthesis coincides with activation of microglia within PVN of angiotensin II-induced hypertensive model and myocardial infarction-induced heart failure model. Although the increase in inflammatory cytokines and the microglial activation within PVN were also seen in spontaneously hypertensive rats (SHR), the model of essential hypertension, their involvement in blood pressure regulation has still be fully clarified. In the present study, we examined whether activated microglia within PVN were involved in maintenance of established severe hypertension with sympathoexcitation. Methods Minocycline (25 mg/kg/day), an inhibitor of microglial activation, or vehicle were orally administered to stroke-prone SHR (SHRSP) and normotensive Wistar-Kyoto (WKY) rats for 2 weeks from 15-weeks-old, the age of established hypertension. Results Systolic blood pressure was comparable between minocycline treated-SHRSP and vehicle treated-SHRSP, whereas morphological analysis of microglia revealed smaller cell size in minocycline treated-SHRSP than vehicle treated-SHRSP, implying that minocycline deactivated microglia within PVN. Conclusions Activated microglia with morphological alteration within PVN are not involved in the maintenance of established severe hypertension, and inflammation within PVN could not be the therapeutic target of established hypertension.

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-1β 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-1β 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-1β.

Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin ΙΙ receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD.In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH.These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD.

Background: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of hypertension (HT) accompanied with chronic kidney disease (CKD). The oxidative stress in the hypothalamus in the brain increases SNA in HT. The renal denervation (RDN) or angiotensin receptor blocker (olmesartan; OLM) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combining RDN and OLM reduces SNA through oxidative stress in the hypothalamus and RAAS in hypertensive mice with CKD. Methods and Results: In 5/6-nephrectomized ICR-mice (Nx, n=19) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased (147±3 vs. 107±3mmHg, p Conclusion: These findings suggest that the OLM/RDN combination therapy have a strong antihypertensive effect associated with inhibiting SNA through reducing oxidative stress in the brain and the plasma aldosterone in hypertensive mice with CKD.

Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT1R) in the brain stem leads to sympathoexcitation due to neuronal AT1R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT1R are only weakly expressed in astrocytes. We hypothesized that AT1R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT1R, we investigated whether AT1R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT1R knockout (GFAP/AT1RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/AT1RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT1RKO mice than in control mice. Prognosis was significantly improved in GFAP/AT1RKO-MI mice compared with control-MI mice. Our findings indicated that AT1R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT1R, AT1R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.

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.

a Department of Cardiovascular Medicine, Kyushu University Hospital, 812-8582, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, Japan b Department of Advanced Cardiovascular Regulation and Therapeutics, Center for Disruptive Cardiovascular Medicine, Kyushu University, 812-8582, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, Japan c Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, 812-8582, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, Japan

Abnormal elevation of blood pressure in early morning (rest-to-active phase) is suggested to cause cardiovascular events. We investigated whether azilsartan (AZL), a novel potent angiotensin receptor blocker, suppresses blood pressure elevation from the light-rest to dark-active phase in spontaneously hypertensive rats (SHRs). AZL has a sustained depressor effect around the rest-to-active phase in SHRs to a greater extent than candesartan (CAN), despite their similar depressor effects for over 24 h. AZL did not cause sympathoexcitation. These results suggest that AZL has a more sustained depressor effect than CAN around the rest-to-active phase in SHRs, and might have advantages for early morning hypertension.

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., 【背景】圧負荷心肥大モデルでは，脳内視床下部におけるミネラルコルチコイド受容体(MR)―アンジオテンシンIIタイプ1受容体(AT1R)経路の活性化により，食塩感受性交感神経活性化と引き続く左心機能低下が生じる．これは，塩分摂取が心不全病態に大きく影響することを示したものである．近年，日本において古来より食されている含塩発酵性調味料である味噌が，食塩感受性高血圧モデルの血圧上昇を軽減することが示されており，本研究において，圧負荷心肥大モデルにおける習慣的味噌摂取の効果を検討した．【方法・結果】2週間の腹部大動脈Bandingにより圧負荷心肥大モデルを作成し(対照群にはSham手術)，その後4週間の食塩水(0.5，1.0，1.5% NaCl)を投与した．24時間尿中カテコラミン排泄量で交感神経活動を評価し，圧負荷心肥大モデルでのみ食塩摂取量に応じた食塩感受性交感神経活性化が生じることを確認した．次に，圧負荷心肥大モデルを用いて，1.0%食塩水摂取群を対照群に，塩分濃度を1.0%に調整した味噌水溶液を4週間投与した．マウスの味噌水溶液摂取量は，1.0%食塩水摂取量よりも多く，Na摂取量の指標である尿中Na排泄量も味噌摂取群で有意に高かった．しかし，味噌摂取群における交感神経活動は1.0%食塩水摂取群に比べて有意に抑制された．また，1.0%食塩水摂取群で認めた心機能低下も味噌摂取群では軽減された．1.0%食塩水摂取群で認めた脳内視床下部におけるMR，serum glucocorticoid-induced kinase-1(MR活性化指標)，AT1R発現も，味噌摂取群では有意に抑制された．【結論】以上より，圧負荷心肥大モデルにおける習慣的味噌摂取は，視床下部MR-AT1R経路活性化の抑制により食塩感受性交感神経活性化を抑制し，心不全を軽減する可能性が示唆される．

We previously reported that pressure overload (PO) activates the hypothalamic mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT1R). Moreover, salt intake further activates the hypothalamic MR and AT1R, resulting in salt-induced sympathoexcitation. However, the mechanism underlying this pathway activation in response to a high salt intake remains unknown. Although the role of aldosterone is extensively examined as a ligand for MR, corticosterone is able to bind to MR. Therefore, we hypothesized that corticosterone contributes to salt-induced sympathoexcitation in PO-mice. Four weeks after aortic banding to produce PO-mice, or a sham operation for controls, the mice were fed a high-salt diet for an additional 4 weeks. Compared to Sham-mice, the expression levels of hypothalamic MR, serum glucocorticoid-induced kinase 1 (a marker of MR activity) and AT1R increased in PO-mice. Salt intake further increased the expression levels of these proteins only in PO-mice with the increases in sympathetic activity evaluated on the basis of the excretion of 24-h urinary norepinephrine excretion. Bilateral adrenalectomy or the intraperitoneal infusion of metyrapone, a corticosterone synthase inhibitor, attenuated salt-induced sympathoexcitation via inhibition of the hypothalamic MR and AT1R activity. These adrenalectomy-induced alterations disappeared after corticosterone replacement therapy. We also found decreased expression levels of 11β-hydroxysteroid dehydrogenase type 2, suggesting that corticosterone is apt to bind to MR. These results indicate that salt intake in PO-mice causes sympathoexcitation via, at least in part, corticosterone-induced MR and AT1R activation in the hypothalamus.

Objectives Enhanced central sympathetic outflow is an indicator of the prognosis of heart failure. Although the central sympatholytic drug moxonidine is an established therapeutic strategy for hypertension, its benefits for hypertensive heart failure are poorly understood. In the present study, we investigated the effects of central sympathoinhibition by intracerebral infusion of moxonidine on survival in a rat model of hypertensive heart failure and the possible mechanisms involved. Methods and results As a model of hypertensive heart failure, we fed Dahl salt-sensitive rats an 8% NaCl diet from 7 weeks of age. Intracerebroventricular (ICV) infusion of moxonidine (moxonidine-ICV-treated group [Mox-ICV]) or vehicle (vehicle-ICV-treated group [Veh-ICV]) was performed at 14-20 weeks of age, during the increased heart failure phase. Survival rates were examined, and sympathetic activity, left ventricular function and remodelling, and brain oxidative stress were measured. Hypertension and left ventricular hypertrophy were established by 13 weeks of age. At around 20 weeks of age, Veh-ICV rats exhibited overt heart failure concomitant with increased urinary norepinephrine (uNE) excretion as an index of sympathetic activity, dilated left ventricle, decreased percentage fractional shortening, and myocardial fibrosis. Survival rates at 21 weeks of age (n = 28) were only 23% in Veh-ICV rats, and 76% (n = 17) in Mox-ICV rats with concomitant decreases in uNE, myocardial fibrosis, collagen type I/III ratio, brain oxidative stress, and suppressed left ventricular dysfunction. Conclusion Moxonidine-induced central sympathoinhibition attenuated brain oxidative stress, prevented cardiac dysfunction and remodelling, and improved the prognosis in rats with hypertensive heart failure. Central sympathoinhibition can be effective for the treatment of hypertensive heart failure.

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. (Circ J 2013; 77: 1474–1481)

It is well established that oxidative stress is involved in the pathogenesis of hypertension. With regard to oxidative stress, however, much attention has been focused on vascular damage in the process of hypertension. In consecutive studies, we have been investigating the role of brain oxidative stress in the central nervous system control of blood pressure. Indeed, we found that oxidative stress is increased in the brain stem, thereby activating the sympathetic nervous system, leading to hypertension. In this chapter, we describe our series of consecutive studies regarding this issue and supporting reports from other laboratories. Because of the importance of sympathetic activation for hypertensive vascular damage, our concepts not only of the pathogenesis but also the therapeutic aspects of hypertension are worthy of attention.

Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates various genes responding to hypoxic conditions. We previously reported that myeloid-specific activation of HIF-1α had protective effects on hypertensive cardiovascular remodelling in mice. However the role of myeloid lineage HIF-1α in the development of abdominal aortic aneurysm (AAA) has not been determined. Myeloid-specific HIF-1α knockout (HIF-1KO) mice were created using a Cre-lox recombination system in the background of apolipoprotein E-deficient (ApoE−/−) mice. HIF-1KO and control mice were fed high-fat diet (HFD) and infused with angiotensin II (Ang II, 1800 ng/kg/min) by an osmotic mini pump for 4 weeks to induce AAA formation. Deletion of HIF-1α increased aortic external diameter (2.47±0.21 mm versus 1.80±0.28 mm in control, P=0.035). AAA formation rate (94.4% in HIF-1KO versus 81.8% in control) was not statistically significant. Elastic lamina degradation grade determined by Elastica van Gieson (EVG) staining was deteriorated in HIF-1KO mice (3.91±0.08 versus 3.25±0.31 in control, P=0.013). The number of infiltrated macrophages into the abdominal aorta was increased in HIF-1KO mice. Expression of tissue inhibitors of metalloproteinases (TIMPs) was suppressed in the aorta and peritoneal macrophages (PMs) from HIF-1KO mice compared with control mice. HIF-1α in myeloid lineage cells may have a protective role against AAA formation induced by Ang II and HFD in ApoE−/− mice.

To prevent cardiovascular events in patients with diabetes mellitus (DM), it is essential to reduce arterial pressure (AP). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) prevents cardiovascular events via the depressor response in patients with DM. In the present study, we examined whether SGLT2i ameliorates AP lability in DM rats. Ten-week-old male Sprague–Dawley rats were administered a single intravenous injection of streptozotocin (50 mg kg−1) and were divided into three groups treated with low-dose SGLT2i, vehicle (VEH) or subcutaneously implanted insulin pellets (SGLT2i, VEH and Insulin group, respectively) for 14 days. SGLT2i reduced blood glucose, but its effect was lower than that of insulin. The telemetered mean AP at the end of the experiment did not differ among the SGLT2i, Insulin and VEH groups (83±7 vs. 98±9 vs. 90±8 mm Hg, respectively, n=5 for each). The standard deviation of AP as the index of lability was significantly smaller during the active period in the SGLT2i group than in the VEH group (5.6±0.5 vs. 7.0±0.7 mm Hg, n=5 for each, P

Increase in cerebrospinal fluid (CSF) Na(+) concentration ([Na(+)]) precedes hypertension and is a key step in the development of salt-induced hypertension. In the choroid plexus (CP), epithelial Na(+) channels (ENaCs) have an important role in Na(+) transport from the blood into the CSF. However, it remains unknown whether the mineralocorticoid receptors (MR)/ENaCs pathway in the CP of stroke-prone spontaneously hypertensive rats (SHRSP) is involved in neural mechanisms of hypertension. Therefore, we examined the role of the MR/ENaCs pathway in the CP in the development of hypertension in SHRSP associated with an increase in CSF [Na(+)]. As a marker of MR activation, serum/glucocorticoid-inducible kinase 1 (Sgk1) expression levels in the CP were measured and found to be greater in SHRSP than in Wistar-Kyoto (WKY) rats. CSF [Na(+)] levels were also higher in SHRSP than in WKY rats. In SHRSP, high-salt intake (8%) increased blood pressure and urinary norepinephrine excretion compared with those in animals fed a regular salt diet (0.5%) for 2 weeks. Furthermore, the expression levels of MR, Sgk1 and ENaCs in the CP and the increase in CSF [Na(+)] were greater in SHRSP fed a high-salt diet than in those fed a regular salt diet. These alterations were attenuated by intracerebroventricular infusion of eplerenone (10 μg kg(-1) per day), except for α-ENaC and β-ENaC. We conclude that activation of the MR/ENaCs pathway in the CP contributes to hypertension via an increase in CSF [Na(+)], thereby exaggerating salt-induced hypertension with sympathetic hyperactivation in SHRSP.

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 β-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.