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April 1998 - present
Publications
Publications (71)
: Mental disorder after myocardial infarction (MI) is reported by many epidemiological studies, and is associated with a poor prognosis. The reduction of brain sigma-1 receptor (S1R) plays an important role in the pathogenesis of mental disorder, and we recently demonstrated that the reduction of brain S1R causes sympathoexcitation. However, the ro...
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....
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...
Introduction:
Increased sympathetic output contributes to cardiac hypertrophy. Sympathoexcitation is induced by activating the cardiac sympathetic afferent nerves through transient receptor potential vanilloid 1 (TRPV1) in cardiac afferent endings. Brainstem nucleus tractus solitarius (NTS) receives the sensory cardiac afferent inputs. Brain-deriv...
Purpose: Left ventricular ejection fraction (LVEF) is commonly measured by echocardiography to evaluate LV function. However, LVEF does not necessarily reflect actual LV function. In fact, half of patients with heart failure have normal LVEF. On the other, plasma brain natriuretic peptide (BNP) is high in those patients and reflects the prognosis....
Objective It is recommended that middle-aged and elderly individuals reduce their salt intake because of the high prevalence of hypertension. The consumption of miso soup is associated with salt intake, and the reduced consumption of miso soup has been recommended. Recent studies have demonstrated that the consumption of miso soup can attenuate an...
A 73-year-old woman presented with diarrhea, leg edema, and exertional dyspnea. Six years before admission, she had been hospitalized for heart failure with moderate-to-severe tricuspid regurgitation because of incomplete leaflet coaptation (Figure 1A; Movie I in the Data Supplement). She was treated with furosemide and has remained on this therapy...
Introduction
Cardiac hypertrophy is an independent risk factor for heart failure, and result in baroreflex dysfunction. Baroreflex dysfunction further deteriorates cardiac hypertrophy and, if prolonged, may progress into heart failure with a vicious cycle. However, it remains unclear how cardiac hypertrophy worsens baroreflex via the heart‐to‐brain...
An 85-year-old woman with chronic kidney disease was referred to us for the examination of a tumour in the left ventricle that was not observed 2 years earlier. She was afebrile associated with negative blood cultures. Transthoracic and transoesophageal echocardiography revealed mitral annular calcification (MAC) and a highly mobile, hyperechoic, a...
Introduction and Hypothesis: Metabolic syndrome (MetS) is often associated with salt-sensitive hypertension. In genetic salt-sensitive hypertensive models, activation of the hypothalamic mineralocorticoid receptor (MR)-epithelial sodium channel (ENaC) pathway has been established as a major worsening factor. However, in MetS, contribution of the hy...
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 p...
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 the activation of the hypothalamic epithelial sodium channels (ENaCs) in heart failure. Here, we stimulated the CSA in adul...
Abstract 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...
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 contribute...
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 centr...
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 intr...
Background
Hypertension causes hypertensive heart failure (HHF). In HHF, excessive sympathoexcitation leads to poor prognosis. However, the effect of central sympathoinhibition on survival in HHF remains unclear. Therefore, we examined whether moxonidine, a sympathoinhibitory agent acting on nischarin associated with oxidative stress, improves prog...
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 re...
Background
Recently, we demonstrated that high‐salt (HS) intake augments sympathetic drive via brain mineralocorticoid receptor (MR) – epithelial Na channels (ENaCs) pathway activation in mice with pressure‐overload (PO‐mice). In the present study, we determined whether imbalance between aldosterone synthesis and activation of cyp2c9‐EET plays a pi...
Background
In salt sensitive models, the increases in cerebrospinal fluid Na ⁺ concentration (CSF [Na]) derived from choroid plexus (CP) play a pivotal role in high salt (HS) induced hypertension. Mineralocorticoid receptors (MR) contribute to Na ⁺ handling. Therefore, we investigated whether MR in CP and paraventricular nucleus of hypothalamus (PV...
Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contribute...
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...
Neuregulin-1 (NRG-1), located in the central nervous system (CNS), plays an important role in synaptic function, neurite outgrowth, and survival of neurons and glia acting on the ErbB receptor family. However, the functional role of NRG-1/ErbB signaling in the CNS and blood pressure regulation is unknown, particularly in the rostral ventrolateral m...
Angiotensin (Ang)-(1-7) Ang-(1-7) is formed from angiotensin II by angiotensin-converting enzyme 2 (ACE2) and modulates the renin-angiotensin system. We evaluated whether the Ang-(1-7)-Mas axis in the rostral ventrolateral medulla (RVLM) contributes to neural mechanisms of blood pressure (BP) regulation. We microinjected Ang-(1-7), Ang-(1-7)-Mas re...
In a pressure overload model, sympathetic activity is augmented in response to salt intake. Mineralocorticoid receptors and epithelial Na channels (ENaCs) are thought to contribute to Na-processing, but the underlying mechanism is unknown. Here, we investigated the contribution of the brain mineralocorticoid receptor- ENaC pathway to salt-induced s...
Background
Neuregulin‐1 (NRG‐1) is a multifunctional modulator that acts through epidermal growth factor family of tyrosine kinase receptors, including erbB2‐4. In the central nervous system, NRG‐1/erbB pathway has been shown to affect both glutamatergic and GABAergic function. However, it is totally unknown if this signaling pathway is involved in...
Background
Increased generation of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) contribute to the neural mechanism of hypertension. The RVLM receives excitatory synaptic inputs from the paraventricular nucleus (PVN). It is also suggested that the angiotensin II type 1 receptors in the RVLM are activated by the PVN stimu...
Background
Angiotensin‐(1‐7) (Ang‐(1‐7)) is recognized as an important mediator of renin angiotensin system. Ang‐(1‐7) is a peptide of ligand for Ang‐(1‐7)‐Mas receptor, and has opposite actions of angiotensin II in the vasculature. In the central nervous system, however, it has been shown that microinjection of Ang‐(1‐7) into rostral ventrolateral...
Radio-frequency catheter ablation (RFCA) was introduced for the treatment of reentrant tachyarrhythmias and has proven its usefulness, efficacy, and safety. It has gained the position of an early stage treatment option rather than being a 'last resort' option for certain groups of patients with supraventricular tachycardias including atrioventricul...
Nitric oxide (NO) in the brainstem modulates blood pressure (BP). Overexpression of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM) increases BP in normotensive Wistar-Kyoto rats (WKY), but its role in BP regulation in spontaneously hypertensive rats (SHR) is unknown. We examined iNOS expression and the effect of iNOS inhib...
In animal models of salt-sensitive hypertension, high salt augments sympathetic outflow via central mechanisms. It is not known, however, whether pressure overload affects salt sensitivity, thereby modifying central sympathetic outflow and cardiac function. We induced left ventricular hypertrophy with aortic banding in mice. Four weeks after aortic...
Background
Statin is consider to protect for neuroplasticity. We demonstrated that oral administration of atorvastatin decreases sympathetic nerve activity (SNA) through the anti‐oxidant effect in rortral ventrolateral medulla (RVLM) of stroke‐prone spontaneously hypertensive rats (SHRSP). We hypothesized that atorvastatin might protect for neuropl...
Salt intake predisposes patients with left ventricular hypertrophy (LVH) to heart failure. We hypothesized that brain Na‐sensitivity increased in patients with LVH. To examine the mechanism of Na‐sensitivity associated with LVH, we performed aortic banding (AB) to produce mice with LVH. Four weeks after AB, 24‐h urinary catecholamine excretion (U‐C...
Background
Neural senescence in brain is progressed by reactive oxygen species (ROS), Ras‐caspase 3‐induced apoptosis and abnormal shortening telomere length, and is associated with neural function. Atorvastatin inhibits sympathetic nerve activity (SNA) by reduction of ROS in rostral ventrolateral medulla (RVLM) of stroke‐prone spontaneously hypert...
Background
Oxidative stress in brain plays a crucial role in the neural mechanism of hypertension. Apolipoprotein E‐knockout mice (apoEKO) reveal increased oxidative stress in the vasculature, heart, and kidney. Aldosterone (ALDO)‐salt load promotes hypertension and organ damage. We hypothesized that apoEKO was susceptible to ALDO‐salt thereby caus...
Background
The small G protein Ras causes caspase‐3 dependent apoptosis through mitogen‐activated protein kinase (MAPK), extracellular signal‐regulated kinase (ERK) and p53. Angiotensin II administered into the rostral ventrolateral medulla (RVLM) induces pressor response through the activation of p38 MAPK and ERK. We hypothesized that Ras‐activate...
Background
In metabolic syndrome (MetS), oxidative stress causes organ damages. Oxidative stress also activates caspase 3‐dependent neural apoptosis and neural senescence progressed by abnormal shortening telomere length. We hypothesized that caspase 3‐dependent apoptosis and telomere‐dependent senescence in brain are activated in MetS.
Methods an...
Background
Activation of the sympathetic nerve activity (SNA) induced by leptin acting on the pituitary‐hypothalamic pathway plays a central role of hypertension in metabolic syndrome (MetS). However, the role of the cardiovascular center in the brain stem (rostral ventrolateral medulla; RVLM) in SNA and the mechanism involved in MetS are not under...
Rho-kinase is involved in the pathogenesis of hypertension and left ventricular remodelling after myocardial infarction (MI). In an earlier study, we had demonstrated that Rho-kinase in the brainstem contributes to hypertensive mechanisms via the sympathetic nervous system; however, it is not known whether Rho-kinase in the brainstem also contribut...
Endothelial function is impaired in hypertensive patients. Decreased nitric oxide production and increased oxidative stress are involved in this abnormality. The aim of the present study was to evaluate whether endothelial function and oxidative stress differ following long-term antihypertensive treatment with an angiotensin type 1 receptor blocker...
Background : We previously demonstrated that oxidative stress is involved in the neural mechanisms of hypertension. In the present study, we evaluated the effects of anti‐hypertensive treatment with the angiotensin type 1 receptor blocker olmesartan on oxidative stress in the brains of stroke‐prone spontaneously hypertensive rats (SHRSP) using the...
Sleep-disordered breathing (SDB) is common in patients with heart failure and carries an independent risk for poor long-term prognosis. We aimed to study the effects of supervised, aerobic exercise training for 6 months on SDB in patients with chronic heart failure.
We enrolled 18 patients having both systolic dysfunction (left ventricular ejection...
This study investigated whether the measurement of mitral annulus displacement by the tissue-tracking method with Doppler-tissue images can provide more accurate information on the severity of heart failure compared to conventional methods, such as left ventricular ejection fraction (LVEF).
Impaired left ventricular function is an important predict...
The brain renin-angiotensin system plays an important role in cardiovascular regulation and the pathogenesis of hypertension. Angiotensin II activates the Rho/Rho-kinase pathway in vascular smooth muscle cells and cardiomyocytes in vitro. The aim of the present study was to determine whether angiotensin II in the brainstem activates the Rho/Rho-kin...
Objectives. The purpose of this study was to determine whether the assessment of mitral annulus displacement (MAD) using Doppler-tissue image (DTI) could provide a useful marker of heart failure severity.[Methods] In seventy-five subjects with heart diseases, we measured MAD by tissue-tracking method with DTI. MAD was evaluated in both septal and l...
Estrogen protects against increases in arterial pressure (AP) by acting on blood vessels and on cardiovascular centers in the brain. The mechanisms underlying the effects of estrogen in the brain stem, however, are not clear. The aim of the present study was to determine whether ovariectomy affects AP via the Rho/Rho-kinase pathway in the brain ste...
Amlodipine is a dihydropyridine calcium channel blocker that is widely used for the treatment of hypertensive patients and has an antioxidant effect on vessels in vitro. The aim of the present study was to examine whether treatment with amlodipine reduced oxidative stress in the brains of stroke-prone spontaneously hypertensive rats (SHRSP). The an...
Reduced nitric oxide (NO) in the brain might contribute to enhanced sympathetic drive in heart failure (HF). The aim of this study was to determine whether increased NO production induced by local overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarius (NTS) of the brain stem reduces the enhanced sympathetic drive in mice...
The Rho/Rho-kinase pathway in the central nervous system is involved in the maintenance of dendritic spines, which form the postsynaptic contact sites of excitatory synapses. Inhibition of the Rho-kinase pathway in neuron promotes dendritic spines or branches. In contrast, activation of the Rho/Rho-kinase pathway reduces dendritic spines or branche...
Rho-kinase is suggested to have an important role in enhanced vasoconstriction in animal models of heart failure (HF). Patients with HF are characterized by increased vasoconstriction and reduced vasodilator responses to reactive hyperemia and exercise. The aim of the present study was to examine whether Rho-kinase is involved in the peripheral cir...
Previously, we reported that the inhibition of Rho-kinase by a microinjection of Y-27632 or the transfection of dominant-negative Rho-kinase into cells of the nucleus tractus solitarii (NTS) reduces blood pressure, heart rate, and sympathetic nerve activity. In the present study, we examined the effects of another Rho-kinase inhibitor, hydroxyfasud...
The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or beta-galactosidase (Adbetagal) were transfected into the RVL...
Previously, we reported that the inhibition of Rho-kinase by a microinjection of Y-27632 or the transfection of dominant-negative Rho-kinase into cells of the nucleus tractus solitarii (NTS) reduces blood pressure, heart rate, and sympathetic nerve activity. In the present study, we examined the effects of another Rho-kinase inhibitor, hydroxyfasud...
The Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem contributes to blood pressure regulation. Activation of this pathway might be involved in the central nervous system mechanisms of hypertension. The aim of the present study was to determine whether baroreflex control of heart rate is altered by inhibition of Rho-ki...
Oxidative stress increases in hypertension. The aim of this study was to determine whether reactive oxygen species (ROS) are increased in the rostral ventrolateral medulla (RVLM) in the brainstem, where the vasomotor center is located, in stroke-prone spontaneously hypertensive rats (SHRSP), and, if so, to determine whether the increased ROS contri...
Central nervous system mechanisms are involved in hypertension caused by chronic inhibition of nitric oxide (NO) synthesis. Chronic inhibition of NO synthesis might also activate the Rho/Rho-kinase pathway in the vasculature. We recently demonstrated that activation of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) contributes to...
Endothelium-derived hyperpolarizing factor (EDHF) contributes to endothelium-dependent relaxation of isolated arteries, but it is not known whether this also occurs in the case of humans in vivo. The present study examined the role of EDHF in human forearm circulation. Forearm blood flow (FBF) was measured by strain-gauge plethysmography in 31 heal...
Pulmonary capillary hemangiomatosis (PCH) is a rare idiopathic lung disorder that occurs in young patients and leads to pulmonary hypertension (PH). It is difficult to diagnosis in the early stage and is often mistaken for primary PH; in almost all cases of PCH, the correct diagnosis is not made until autopsy. In the present case of PCH, the patien...
Recent studies have demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, including actin cytoskeleton organization and vascular smooth muscle contraction. This pathway is also present in the central nervous system and is involved in the maintenance of dendritic spines and axon outgrowth and in the regu...
Previously, we demonstrated that endothelial nitric oxide synthase (eNOS) gene transfer into the nucleus tractus solitarii (NTS) decreased blood pressure, heart rate and sympathetic nerve activity in conscious normotensive Wistar-Kyoto rats (WKY). In order to determine whether overexpression of eNOS in the NTS causes different effects on blood pres...
We previously demonstrated that the overexpression of endothelial nitric oxide synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate (HR), and sympathetic nerve activity and that these effects are enhanced in stroke-prone spontaneously hypertensive rats (SHRSP). The aim of this study was to determine if an...
We have previously demonstrated that the overexpression of endothelial NO synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate, and sympathetic nerve activity via an increase in gamma-amino butyric acid release in normotensive Wistar-Kyoto rats (WKY). Stroke-prone spontaneously hypertensive rats (SHRSP) a...
