Fusakazu Jo

Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment

Resveratrol is known to improve endothelial function in animals, but little is known about its effect on human subjects. Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors underlying endothelial dysfunction. We hypothesized that the modified resveratrol, Longevinex, improves endothelial function in patients with MetS. Thirty-four patients who had been treated for MetS and lifestyle-related disease were randomly assigned to group A, in which Longevinex was administered for 3 months and then discontinued for 3 months, whereas in the time-matched group B, Longevinex was administered between 3 and 6 months. These 2 groups of patients received similar drugs at baseline for diabetes mellitus, dyslipidemia, or hypertension. Flow-mediated dilatation significantly increased during the administration of Longevinex but decreased to baseline 3 months after the discontinuation of Longevinex in the group A patients. Conversely, in the group B patients, flow-mediated dilatation remained unchanged for the first 3 months without Longevinex but was significantly increased 3 months after the treatment with Longevinex. Longevinex did not significantly affect blood pressure, insulin resistance, the lipid profile or inflammatory markers during 6-month follow-up. These results demonstrate that Longevinex specifically improves endothelial function in subjects with MetS who were receiving standard therapy for lifestyle-related disease.

Prognostic Significance of Ankle-Brachial Index, Brachial-Ankle Pulse Wave Velocity, Flow-Mediated Dilation, and Nitroglycerin-Mediated Dilation in End-Stage Renal Disease

Background: Identifying patients at high risk of cardiovascular disease is important in managing patients undergoing hemodialysis. Methods: We evaluated a series of prognostic values: flow-mediated dilation (FMD) and nitrogen-mediated dilation (NMD), an index of endothelium-dependent and endothelium-independent function, respectively, ankle-brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV) in patients undergoing chronic hemodialysis. Results: A cohort of 199 patients was studied. At entry, these values were examined and the prognostic significances were investigated. In estimating the significance of baPWV, patients with ABI <0.9 were excluded. During the follow-up period, 24 deaths occurred including 14 cardiovascular and 10 noncardiovascular fatal events. Overall, the survival rates were significantly lower in the low ABI than in the high ABI group, but the survival rates were not significantly different between the high and low FMD, NMD, or baPWV groups. Cardiovascular survival rates were significantly lower in the low ABI than in the high ABI group, and in the high baPWV than in the low baPWV group. The survival rates were not significantly different between the high and low FMD or NMD groups. Conclusions: Screening hemodialysis patients by means of ABI and baPWV but not FMD or NMD provides complementary information in identifying a high-risk population in these patients.

Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice

1. Uncoupling of nitric oxide synthase (NOS) has been implicated in the pathogenesis of left ventricular (LV) dysfunction in diabetes mellitus. In the present study, we investigated the role of NOS uncoupling in oxidative/nitrosative stress and LV dysfunction in the diabetic mouse heart.

Risk Factors of Normal Ankle–Brachial Index and Low Toe–Brachial Index in Hemodialysis Patients

The prevalence of peripheral arterial occlusive disease is high in patients with terminal renal failure, and it is a major problem in those on dialysis. A low ankle–brachial index (ABI) suggests the presence of arterial stenotic lesions between the aorta and the ankle joint, while a low toe–brachial index (TBI) suggests stenotic lesions between the aorta and the toes. Therefore, a normal ABI (≥0.9) and a low TBI (<0.6) may indicate the presence of stenotic lesions located only on the peripheral side of the ankle joint. In the present study, risk factors of normal ABI/low TBI were investigated. In 115 patients on maintenance dialysis, the ABI and TBI were simultaneously measured, and the background factors and laboratory data of patients with normal ABI/low TBI (L group) and those with normal ABI/normal TBI (≥0.6) (N group) were compared. Low ankle–brachial and toe–brachial indices were detected in 13% and 22% of the patients, respectively. Comparison of the background factors and laboratory data between the N and L groups showed that the ratio of diabetes mellitus, interdialytic body weight gain, and HbA1c values were significantly higher in the L group than in the N group. It was clarified that diabetes and excess body weight gain are involved as risk factors in dialysis patients with normal ABI/low TBI.

Brain Endoplasmic Reticulum Stress Mechanistically Distinguishes the Saline-Intake and Hypertensive Response to Deoxycorticosterone Acetate–Salt

Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)–salt. Intracerebroventricular delivery of the endoplasmic reticulum stress–reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein–deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt–induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein–deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt–induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure.

Efficacy of an L- and N-type calcium channel blocker in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla

The rostral ventrolateral medulla is an important regulation center of sympathetic nerve activity. Several clinical studies have indicated a possible association between essential hypertension and neurovascular compression of the rostral ventrolateral medulla. We have found that patients with essential hypertension and neurovascular compression of the rostral ventrolateral medulla by adjacent arteries have increased sympathetic nerve activity and that microvascular decompression of the rostral ventrolateral medulla normalizes blood pressure and sympathetic nerve activity. Although sympatholytic agents are expected to lower blood pressure in these patients, this remains to be clarified. In this study, we evaluated the effect of cilnidipine, a calcium channel blocker that blocks both vascular L-type and sympathetic N-type Ca2+ channels in hypertensive patients with neurovascular compression. Using high-resolution magnetic resonance imaging, 46 patients with untreated essential hypertension were distributed into those with and without neurovascular compression of the rostral ventrolateral medulla. All patients were prescribed 10 mg of cilnidipine for 16 weeks. Office and home blood pressure, plasma norepinephrine and left ventricular mass index were measured by echocardiography before and after cilnidipine treatment, and changes were compared between the two groups. At baseline, plasma norepinephrine was significantly higher in patients with neurovascular compression. Decreases in office and home blood pressure, plasma norepinephrine and left ventricular mass index were significantly greater in patients with neurovascular compression. These results suggest that cilnidipine lowers blood pressure by inhibiting enhanced sympathetic nerve activity and reduces left ventricular mass in hypertensive patients with neurovascular compression of the rostral ventrolateral medulla.

Characteristics of 20-Year Survivors Undergoing Maintenance Hemodialysis

Hemodialysis techniques have improved remarkably in recent decades and the number of long‐term survivors among patients with end‐stage renal disease has increased. The mortality rate of hemodialysis patients has been reported to be low in Japan. However, the long‐term survival rate of dialysis patients is still low: 23.6% for 15 years and 17.4% for 20 years, even in Japan, and background information on patients undergoing hemodialysis therapy for more than 20 years is scarce in this country. In the present study, we investigated the characteristics of 20‐year survivors undergoing maintenance hemodialysis at our medical center. We compared the characteristics of hemodialysis patients who had survived for more than 20 years after the initiation of hemodialysis with those of patients who started hemodialysis at the same time and had already died. No patient among those who were still alive had diabetes mellitus while 15% of patients who had died had diabetes mellitus at the time of initiation of hemodialysis. Age, cardiothoracic ratio, and serum levels of total cholesterol and triglyceride 6 months after the initiation of hemodialysis, as well as decreases in body weight per year were significantly lower in those who had survived than in those who had died. These results suggest that long‐term hemodialysis survivors are characterized by (i) initiation of hemodialysis at a young age (ii) being free of diabetes mellitus (iii) a well‐controlled cardiothoracic ratio (iv) small successive change in body weight, and (v) being free of hypercholesterolemia and hypertriglyceridemia.

Olmesartan Induces Renoprotective Effects by Stimulating Angiotensin Type 2 Receptors and Reducing Oxidative Stress in Diabetic Nephropathy

Background: Angiotensin receptor blockers reduce the progression of diabetic nephropathy primarily by inhibiting angiotensin type 1 (AT1) receptors. In the present study, we investigated the role of angiotensin type 2 (AT2) receptors on the renoprotective effects of olmesartan in diabetic nephropathy. Methods: Six-week-old mice were treated with streptozotocin and divided into four groups: the OLM group (mice treated with olmesartan), the OLM+Ang II group (mice treated with olmesartan and angiotensin II), the OLM+PD group (mice treated with olmesartan and the AT2 antagonist PD 123319), and the vehicle group. Nondiabetic mice were used as controls. We measured blood glucose levels and urinary excretions of albumin and 8-hydroxy-2’-deoxyguanosine (8-OHdG), which is a marker for oxidative stress. Results: Although urinary albumin excretion in the OLM and OLM+Ang II groups showed a tendency to be reduced compared to the vehicle group, it was significantly lower compared to the OLM+PD group. Urinary excretion of 8-OHdG was also significantly lower in the OLM and OLM+Ang II groups compared to the OLM+PD group. Conclusions: In diabetic nephropathy, the renoprotective effects of olmesartan are due not only to the blockade of AT1 receptors, but also to a reduction in oxidative stress via stimulation of AT2 receptors.

Brain Endoplasmic Reticulum Stress Mechanistically Distinguishes the Saline-Intake and Hypertensive Response to DOCA-Salt

Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)–salt. Intracerebroventricular delivery of the endoplasmic reticulum stress–reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein–deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt–induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein–deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt–induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure.

Brain Endoplasmic Reticulum Stress Mechanistically Distinguishes the Saline-Intake and Hypertensive Response to Deoxycorticosterone Acetate–SaltNovelty and Significance

Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)–salt. Intracerebroventricular delivery of the endoplasmic reticulum stress–reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein–deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt–induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein–deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt–induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure.