Aspirin for Stroke Prevention in Elderly Patients With Vascular Risk Factors: Japanese Primary Prevention Project.

BACKGROUND AND PURPOSE: The effect of aspirin in primary prevention of stroke is controversial among clinical trials conducted in Western countries, and no data are available for Asian populations with a high risk of intracranial hemorrhage. The objective of this study was to evaluate the effect of aspirin on the risk of stroke and intracranial hemorrhage in the Japanese Primary Prevention Project (JPPP). METHODS: A total of 14 464 patients (age, 60-85 years) with hypertension, dyslipidemia, and diabetes mellitus participated and were randomized into 2 treatment groups: 100 mg of aspirin or no aspirin. The median follow-up period was 5.02 years. RESULTS: The cumulative rate of fatal or nonfatal stroke was similar for the aspirin (2.068%; 95% confidence interval [CI], 1.750-2.443) and no aspirin (2.299%; 95% CI, 1.963-2.692) groups at 5 years; the estimated hazard ratio was 0.927 (95% CI, 0.741-1.160; P=0.509). Aspirin nonsignificantly reduced the risk of ischemic stroke or transient ischemic attack (hazard ratio, 0.783; 95% CI, 0.606-1.012; P=0.061) and nonsignificantly increased the risk of intracranial hemorrhage (hazard ratio, 1.463; 95% CI; 0.956-2.237; P=0.078). A Cox regression adjusted by the risk factors for all stroke, which were age >70 years, smoking, and diabetes mellitus, supported the above result. CONCLUSIONS: Aspirin did not show any net benefit for the primary prevention of stroke in elderly Japanese patients with risk factors for stroke, whereas age >70 years, smoking, and diabetes mellitus were risk factors for stroke regardless of aspirin treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00225849.

Phylogenetic and Geographic Relationships of Severe Fever With Thrombocytopenia Syndrome Virus in China, South Korea, and Japan.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne acute infectious disease caused by the SFTS virus (SFTSV). SFTS has been reported in China, South Korea, and Japan as a novel Bunyavirus. Although several molecular epidemiology and phylogenetic studies have been performed, the information obtained was limited, because the analyses included no or only a small number of SFTSV strains from Japan. METHODS: The nucleotide sequences of 75 SFTSV samples in Japan were newly determined directly from the patients' serum samples. In addition, the sequences of 7 strains isolated in vitro were determined and compared with those in the patients' serum samples. More than 90 strains that were identified in China, 1 strain in South Korea, and 50 strains in Japan were phylogenetically analyzed. RESULTS: The viruses were clustered into 2 clades, which were consistent with the geographic distribution. Three strains identified in Japan were clustered in the Chinese clade, and 4 strains identified in China and 26 in South Korea were clustered in the Japanese clade. CONCLUSIONS: Two clades of SFTSV may have evolved separately over time. On rare occasions, the viruses were transmitted overseas to the region in which viruses of the other clade were prevalent.

High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice.

BACKGROUND: It is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome. METHODS: We examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice. RESULTS: High-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice. CONCLUSIONS: We demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.

Sensitive and specific PCR systems for detection of both Chinese and Japanese severe fever with thrombocytopenia syndrome virus strains and prediction of patient survival based on viral load.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high case fatality risk and is caused by the SFTS virus (SFTSV). A retrospective study conducted after the first identification of an SFTS patient in Japan revealed that SFTS is endemic to the region, and the virus exists indigenously in Japan. Since the nucleotide sequence of Japanese SFTSV strains contains considerable differences compared with that of Chinese strains, there is an urgent need to establish a sensitive and specific method capable of detecting the Chinese and Japanese strains of SFTSV. A conventional one-step reverse transcription-PCR (RT-PCR) (cvPCR) method and a quantitative one-step RT-PCR (qPCR) method were developed to detect the SFTSV genome. Both cvPCR and qPCR detected a Chinese SFTSV strain. Forty-one of 108 Japanese patients suspected of having SFTS showed a positive reaction by cvPCR. The results from the samples of 108 Japanese patients determined by the qPCR method were in almost complete agreement with those determined by cvPCR. The analyses of the viral copy number level in the patient blood samples at the acute phase determined by qPCR in association with the patient outcome confirmed that the SFTSV RNA load in the blood of the nonsurviving patients was significantly higher than that of the surviving patients. Therefore, the cvPCR and qPCR methods developed in this study can provide a powerful means for diagnosing SFTS. In addition, the detection of the SFTSV genome level by qPCR in the blood of the patients at the acute phase may serve as an indicator to predict the outcome of SFTS.

Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in Renin-Angiotensin System (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) study.

OBJECTIVE: This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). METHODS: In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. RESULTS: Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). CONCLUSIONS: The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial.

IMPORTANCE: Prevention of atherosclerotic cardiovascular diseases is an important public health priority in Japan due to an aging population. OBJECTIVE: To determine whether daily, low-dose aspirin reduces the incidence of cardiovascular events in older Japanese patients with multiple atherosclerotic risk factors. DESIGN, SETTING, AND PARTICIPANTS: The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Patients (N = 14,464) were aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus recruited by primary care physicians at 1007 clinics in Japan between March 2005 and June 2007, and were followed up for up to 6.5 years, with last follow-up in May 2012. A multidisciplinary expert panel (blinded to treatment assignments) adjudicated study outcomes. INTERVENTIONS: Patients were randomized 1:1 to enteric-coated aspirin 100 mg/d or no aspirin in addition to ongoing medications. MAIN OUTCOMES AND MEASURES: Composite primary outcome was death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal myocardial infarction. Secondary outcomes included individual end points. RESULTS: The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55-5.33) based on likely futility. In both the aspirin and no aspirin groups, 56 fatal events occurred. Patients with an occurrence of nonfatal stroke totaled 114 in the aspirin group and 108 in the no aspirin group; of nonfatal myocardial infarction, 20 in the aspirin group and 38 in the no aspirin group; of undefined cerebrovascular events, 3 in the aspirin group and 5 in the no aspirin group. The 5-year cumulative primary outcome event rate was not significantly different between the groups (2.77% [95% CI, 2.40%-3.20%] for aspirin vs 2.96% [95% CI, 2.58%-3.40%] for no aspirin; hazard ratio [HR], 0.94 [95% CI, 0.77-1.15]; P = .54). Aspirin significantly reduced incidence of nonfatal myocardial infarction (0.30 [95% CI, 0.19-0.47] for aspirin vs 0.58 [95% CI, 0.42-0.81] for no aspirin; HR, 0.53 [95% CI, 0.31-0.91]; P = .02) and transient ischemic attack (0.26 [95% CI, 0.16-0.42] for aspirin vs 0.49 [95% CI, 0.35-0.69] for no aspirin; HR, 0.57 [95% CI, 0.32-0.99]; P = .04), and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization (0.86 [95% CI, 0.67-1.11] for aspirin vs 0.51 [95% CI, 0.37-0.72] for no aspirin; HR, 1.85 [95% CI, 1.22-2.81]; P = .004). CONCLUSIONS AND RELEVANCE: Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225849.

Kidney transplantation restored uncoupled bone turnover in end-stage renal disease.

BACKGROUND: While kidney transplantation (KTx) reverses many disorders associated with end-stage renal disease (ESRD), patients who have received KTx often have chronic kidney disease and bone and mineral disorder (CKD-MBD). However, it is unknown how bone metabolism changes by KTx. PATIENTS AND METHODS: Living donor-KTx recipients (n = 34) at Tokyo Women's Medical University were prospectively recruited and the levels of bone-specific alkaline phosphatase (BAP) and serum cross-linked N-telopeptides of Type 1 collagen (NTX) were measured before, 6 and 12 months after transplantation. RESULTS: Before KTx, serum BAP was within the reference range in more than half of patients while NTX was high in most patients. Serum NTX was higher in patients with longer dialysis durations compared to that with shorter durations before KTx. However, there was no difference in serum BAP between these patients. After KTx, BAP increased while NTX decreased along with the decline of PTH. In addition, the numbers of patients who showed high BAP and NTX were comparable after KTx. CONCLUSION: These results suggest that bone formation is suppressed and uncoupled with bone resorption in patients with ESRD and this uncoupling is restored by KTx. Further studies are necessary to clarify the mechanism of bone uncoupling in patients with ESRD.

Reactive oxygen species and the central nervous system in salt-sensitive hypertension: possible relationship with obesity-induced hypertension.

1. There are multiple and complex mechanisms of salt-induced hypertension; however, central sympathoexcitation plays an important role. In addition, the production of reactive oxygen species (ROS) is increased in salt-sensitive hypertensive humans and animals. Thus, we hypothesized that brain ROS overproduction may increase blood pressure (BP) by central sympathostimulation. 2. Recently, we demonstrated that ROS levels were elevated in the hypothalamus of salt-sensitive hypertensive animals. Moreover, intracerebroventricular anti-oxidants suppressed BP and renal sympathetic nerve activity more in salt-sensitive than non-salt-sensitive hypertensive rats. Thus, brain ROS overproduction increased BP through central sympathoexcitation in salt-sensitive hypertension. 3. Salt sensitivity of BP is enhanced in obesity and metabolic syndrome. Interestingly, it is also suggested that, in obesity-induced hypertension models, increases in BP are caused by brain ROS-induced central sympathoexcitation. 4. Recent studies suggest that increased ROS production in the brain and central sympathoexcitation may share a common pathway that increases BP in both salt- and obesity-induced hypertension.

Mineralocorticoid receptor activation: a major contributor to salt-induced renal injury and hypertension in young rats.

Excessive salt intake is known to preferentially increase blood pressure (BP) and promote kidney damage in young, salt-sensitive hypertensive human and animal models. We have suggested that mineralocorticoid receptor (MR) activation plays a major role in kidney injury in young rats. BP and urinary protein were compared in young (3-wk-old) and adult (10-wk-old) uninephrectomized (UNx) Sprague-Dawley rats fed a high (8.0%)-salt diet for 4 wk. The effects of the MR blocker eplerenone on BP and renal injury were examined in the high-salt diet-fed young UNx rats. Renal expression of renin-angiotensin-aldosterone (RAA) system components and of inflammatory and oxidative stress markers was also measured. The effects of the angiotensin receptor blocker olmesartan with or without low-dose aldosterone infusion, the aldosterone synthase inhibitor FAD286, and the antioxidant tempol were also studied. Excessive salt intake induced greater hypertension and proteinuria in young rats than in adult rats. The kidneys of young salt-loaded rats showed marked histological injury, overexpression of RAA system components, and an increase in inflammatory and oxidative stress markers. These changes were markedly ameliorated by eplerenone treatment. Olmesartan also ameliorated salt-induced renal injury but failed to do so when combined with low-dose aldosterone infusion. FAD286 and tempol also markedly reduced urinary protein. UNx rats exposed to excessive salt at a young age showed severe hypertension and renal injury, likely primarily due to MR activation and secondarily due to angiotensin receptor activation, which may be mediated by inflammation and oxidative stress.

Design and rationale of Japanese evaluation between Formula of Azelnidipine and amlodipine add on olmesartan to Get antialbuminuric effect study (J-FLAG) : evaluation of the antialbuminuric effects between calcium channel blocker with sympatholytic action in hypertensive patients with diabetes and albuminuria.

PURPOSE: Calcium channel blockers (CCBs) are recommended second-line antihypertensives for renin-angiotensin system (RAS) inhibitor-treated patients with chronic kidney disease (CKD), but they do not always ameliorate the progression of CKD. However, small clinical studies suggest that sympatholytic CCBs may protect against kidney injury. Therefore, a clinical trial was designed to test whether the sympatholytic CCB azelnidipine decreases the urinary albumin levels of CKD patients treated with the angiotensin receptor blocker olmesartan more potently than the widely-used non-sympatholytic CCB amlodipine. METHODS: A multi-center, open-labeled, randomized clinical intervention trial was designed to compare the antialbuminuric effect of azelnidipine (8-16 mg/day) and amlodipine (2.5-5 mg/day) in olmesartan-treated hypertensive (blood pressure 130-180/80-110 mmHg) patients with type 2 diabetes (fasting blood sugar ≥126 mg/dL or treatment with antidiabetic agents) and albuminuria (urinary albumin/creatinine ratio ≥30 mg/g). The primary study endpoint is the change in the urinary albumin/creatinine ratio after 12 months of treatment. CONCLUSIONS: The present trial is expected to clarify whether the sympatholytic CCB azelnidipine is a beneficial second-line choice for RAS inhibitor-treated hypertensive patients with CKD, such as diabetic nephropathy.

Renal preservation effect of ubiquinol, the reduced form of coenzyme Q10.

BACKGROUND: The aim of this study was to evaluate the renal preservation effect of ubiquinol, the reduced form of coenzyme Q10 (CoQ10). METHODS: Three-week-old heminephrectomized male Sprague-Dawley rats were divided into three groups (10 animals each): diet with normal (0.3%) salt, high (8%) salt, and high salt plus 600 mg/kg body weight/day of ubiquinol, for 4 weeks. Systolic blood pressure (SBP), urinary albumin (u-alb), superoxide anion generation (lucigenin chemiluminescence) and ubiquinol levels in renal tissues were examined. RESULTS: Salt loading increased SBP (111.0 ± 3.6 vs. 169.4 ± 14.3 mmHg, p < 0.01) and u-alb (43.8 ± 28.0 vs. 2528.7 ± 1379.0 µg/day, p < 0.02). These changes were associated with stimulation of superoxide generation in the kidney (866.3 ± 102.8 vs. 2721.4 ± 973.3 RLU/g kidney, p < 0.01). However, ubiquinol decreased SBP (143.9 ± 29.0 mmHg, p < 0.05), u-alb (256.1 ± 122.1 µg/day, p < 0.02), and renal superoxide production (877.8 ± 195.6 RLU/g kidney, p < 0.01), associated with an increase in renal ubiquinol levels. CONCLUSION: Ubiquinol, the reduced form of CoQ10, effectively ameliorates renal function, probably due to its antioxidant effect. Thus, ubiquinol may be a candidate for the treatment of patients with kidney disease.

Design and rationale of the study of assessment for kidney function by urinary microalbumin in randomized (SAKURA) trial.

Recently, it has been demonstrated that L-/N-type calcium channel blockers (CCBs), cilnidipine, but not L-type CCB, decreased urinary protein in renin-angiotensin system (RAS), inhibitor-treated hypertensive patients with macroproteinuria. However, the antiproteinuric effect of cilnidipine was weaker in diabetic patients than in nondiabetic patients with macroproteinuria. This may be due to the fact that diabetic neuropathy was also developed in patients with advanced diabetic nephropathy because L-/N-type CCB has been considered to exert its renoprotetive effects through sympatholytic action. If so, the antiproteinuric effect of cilnidipine may be potent in patients with early stages of diabetic nephropathy. To elucidate our hypothesis, we designed a multi-center, open-labeled, randomized trial to compare the antialbuminuric effect between cilnidipine and amlodipine in RAS inhibitor-treated hypertensive (blood pressure [BP]: 130-180/80-110 mmHg) patients with type 2 diabetes and microalbuminuria (urinary albumin/creatinine [Cr] ratio: 30-300 mg/g). The primary study endpoint is the change in the urinary albumin/Cr ratio after a 1-year treatment. Enrollment began in April 2008 and was completed in March 2010. A total of 367 patients were randomly allocated to receive cilnidipine or amlodipine. At baseline, study subjects had 63.3± 8.5 years of age, 145.9 ± 12.2/80.8 ± 10.0 mmHg of BP, 101.0 ± 111.6 mg/g of urinary albumin/Cr. The trial is expected to show whether cilnidipine can exert an antialbuminuric effect in RAS inhibitor-treated hypertensive patients with early stages of diabetic nephropathy.

Chiral Silica with Preferred-Handed Helical Structure via Chiral Transfer.

A strategy to obtain chiral silica using an achiral stereoregular polymer with polyhedral oligomeric silsesquioxane (POSS) side chains is described herein. The preferred helical conformation of the POSS-containing polymer could be achieved by mixing isotactic polymethacrylate-functionalized POSS (it-PMAPOSS) and a chiral dopant. The array structure of POSS molecules, which are placed along the helical conformation, is memorized even after removing the chiral dopant at high temperatures, leading to a chiral silica compound with exclusive optical activity after calcination.

Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension.

BACKGROUND: Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension. METHODS AND RESULTS: Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 mumol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. Central tempol reduced arterial pressure and renal sympathetic nerve activity to a significantly greater extent in high-fat diet-fed hypertensive rats than in low-fat diet-fed normotensive rats. Intracerebroventricular apocynin or diphenyleneiodonium, a reduced NADPH oxidase inhibitor, also elicited markedly greater reductions in arterial pressure and renal sympathetic nerve activity in the high-fat diet-fed rats. In addition, fat loading increased NADPH oxidase activity and NADPH oxidase subunit p22(phox), p47(phox), and gp91(phox) mRNA expression in the hypothalamus. CONCLUSIONS: In obesity-induced hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, may contribute to the progression of hypertension through central sympathoexcitation.

Rationale, design, and baseline data of the Japanese Primary Prevention Project (JPPP)-a randomized, open-label, controlled trial of aspirin versus no aspirin in patients with multiple risk factors for vascular events.

BACKGROUND: Prevention of atherosclerotic disease has become an important public health priority in Japan due to the aging of the population and changes in diet and lifestyle factors. METHODS: The Japanese Primary Prevention Project (JPPP) is a multicenter, open-label, randomized, parallel-group trial that is evaluating primary prevention with low-dose aspirin in Japanese patients aged 60 to 85 years with hypertension, dyslipidemia, or diabetes mellitus. The study cohort will be followed for a mean of 4 years. The primary end point is a composite of death from cardiovascular causes (including fatal myocardial infarction [MI], fatal stroke, and other cardiovascular death), nonfatal stroke (ischemic or hemorrhagic), and nonfatal MI. Key secondary end points include a composite of cardiovascular death, nonfatal stroke, nonfatal MI, transient ischemic attack, angina pectoris, or arteriosclerotic disease requiring surgery or intervention; each component of the primary end point; noncerebrovascular and noncardiovascular death; and extracranial hemorrhage requiring transfusion or hospitalization. End point assessment is done by a central adjudication committee that is blinded to treatment assignments. RESULTS: Enrollment began in March 2005 and was completed in June 2007. A total of 14,466 patients were randomly allocated to receive enteric-coated aspirin, 100 mg/d, or no aspirin. At randomization, the study cohort had a mean (SD) age of 70.6 (6.2) years; 57.8% were women, 85.0% had hypertension, 71.7% had dyslipidemia, and 33.9% had diabetes. In the study cohort, 80.4% of patients had > or =3 risk factors. CONCLUSION: The JPPP is the largest primary prevention trial of aspirin in a Japanese population that is investigating whether the benefit of aspirin in reducing risk of vascular events outweighs any bleeding risk in elderly patients with multiple risk factors.

Mineralocorticoid receptor activation contributes to salt-induced hypertension and renal injury in prepubertal Dahl salt-sensitive rats.

BACKGROUND: Excessive prepubertal salt intake permanently increases blood pressure (BP). We examined the role that the mineralocorticoid receptor (MR) plays in the salt-induced hypertension and renal damage of prepubertal Dahl salt-sensitive (SS) rats. METHODS: Prepubertal (6 weeks old) and adult (10 weeks old) Dahl SS rats fed a high (8.0%) salt (HS) diet for 10 weeks were compared in terms of BP and renal function. The effect of treatment between the ages of 4 and 10 weeks with the MR antagonist eplerenone (0.125% in chow), the vasodilator hydralazine (50 mg/kg/day in drinking water) or the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (tempol) (0.6 mmol/kg/day in drinking water) on the BP and renal function of prepubertal rats fed a HS diet for 10 weeks was also examined. RESULTS: Excessive salt intake starting in prepuberty was associated with a higher BP increase and greater proteinuria than if it started in adulthood. Eplerenone moderately reduced BP and markedly improved renal injury during its administration in prepubertal rats. These effects continued after drug discontinuation. Hydralazine greatly decreased BP and reduced proteinuria, but these effects were completely lost after drug discontinuation. Excessive salt increased urinary 8-hydroxy-2'-deoxyguanosine levels, intrarenal macrophage infiltration and renal plasminogen activator inhibitor-1 and transforming growth factor-beta mRNA expression. Eplerenone, but not hydralazine, attenuated these salt-induced inflammatory reactions. Tempol improved salt-induced hypertension and renal injury, even after its discontinuation. CONCLUSIONS: Dahl SS rats exposed to excessive salt in prepubescence show a permanent increase in susceptibility to salt-induced hypertension and proteinuria. MR activation may promote these effects at least in part by inducing oxidation and inflammation.

Antioxidant, EUK-8, prevents murine dilated cardiomyopathy.

BACKGROUND: Mice lacking manganese-superoxide dismutase (Mn-SOD) activity exhibit the typical pathology of dilated cardiomyopathy (DCM). In the present study, presymptomatic and symptomatic mutant mice were treated with the SOD/catalase mimetic, EUK-8. METHODS AND RESULTS: Presymptomatic heart/muscle-specific Mn-SOD-deficient mice (H/M-Sod2(-/-)) were treated with EUK-8 (30 mg x kg(-1) . day(-1)) for 4 weeks, and then cardiac function and the reactive oxygen species (ROS) production in their heart mitochondria were assessed. EUK-8 treatment suppressed the progression of cardiac dysfunction and diminished ROS production and oxidative damage. Furthermore, EUK-8 treatment effectively reversed the cardiac dilatation and dysfunction observed in symptomatic H/M-Sod2(-/-) mice. Interestingly, EUK-8 treatment repaired a molecular defect in connexin43. CONCLUSIONS: EUK-8 treatment can prevent and cure murine DCM, so SOD/catalase mimetic treatment is proposed as a potential therapy for DCM.

Effect of high fat loading in Dahl salt-sensitive rats.

Salt sensitivity of blood pressure (BP) is speculated to be a characteristic in obesity-induced hypertension. To elucidate the influence of obesity on salt-sensitive hypertension, we examined the effect of fat loading on BP, renal damage, and their progression induced by salt excess in Dahl salt-sensitive (S) rats. High fat (HF: 45% fat diet: 8 weeks) diet increased BP with greater weight gain and visceral fat accumulation than low fat (10% fat) diet. In HF-fed rats, plasma glucose, plasma insulin, and urinary catecholamine increased, and urinary protein tended to be elevated. Moreover, excessive salt (8% salt diet: 8 weeks)-induced hypertension and proteinuria was accelerated in HF-fed rats. Therefore, fat loading increased BP in Dahl S rats possibly through insulin-resistance and sympathetic excitation. Moreover, fat loading accelerated salt-induced BP elevation and renal damage, suggesting excessive intake of both fat and salt, such as a civilized diet, exert the synergic harmful effects.

Influence of blood pressure on the effects of low-dose asprin in elderly patients with multiple atherosclerotic risks.

OBJECTIVE: We examined whether the efficacy of low-dose acetylsalicylic acid (aspirin) for primary prevention of cardiovascular events is influenced by blood pressure (BP) using data from patients aged 60-85 years with hypertension, dyslipidemia, and/or diabetes, but without cardiovascular disease of the Japanese Primary Prevention Project. METHODS: All patients had received aspirin (100 mg/day) or no aspirin. BP subgroups were defined as low (average SBP from the baseline to the year of the events <130 mmHg), moderate (≥130 and <140 mmHg), and high (≥140 mmHg). The mean duration of follow-up was 5.02 years. RESULTS: In hypertensive patients (n = 12 278) aspirin had no significant impact on the primary outcome of death from cardiovascular disease, nonfatal stroke, and nonfatal myocardial infarction. On the other hand, aspirin increased the incidence of serious extracranial hemorrhage [hazard ratio, 1.81; 95% confidence interval (CI), 1.18-2.77; P = 0.0064] and tended to increase hemorrhagic stroke (hazard ratio, 1.75; CI, 0.99-3.07; P = 0.053). Aspirin had no effect on the primary outcome in any of the BP subgroups, and was associated with increased hemorrhagic stroke in the high BP group (hazard ratio, 3.51; CI, 1.29-9.51; P = 0.014); serious extracranial hemorrhage was elevated or tended to elevate in the moderate (hazard ratio, 2.53; CI, 1.18-5.45; P = 0.017) and high (hazard ratio, 2.14; CI, 1.00-4.56; P = 0.050) BP groups. CONCLUSION: In aged Japanese hypertensive patients, these data demonstrated no overall benefit of low-dose aspirin therapy although treatment was associated with an elevated risk of hemorrhagic events.