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The Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study and its pooled analysis showed that intensive blood pressure (BP) lowering reduced recurrent stroke risk by 22% in patients with a history of stroke. Here, we report the effect of intensive BP lowering on the risk of recurrent stroke subtypes in patients with a history of ischemic stroke. RESPECT was a randomized clinical trial among 1280 people with a history of cerebral infarction or intracerebral hemorrhage. Participants were assigned to the intensive blood pressure control group (blood pressure120/80 mmHg) or standard blood pressure control group (blood pressure140/90 mmHg). In this post hoc analysis, we analyzed 1074 patients with a history of cerebral infarction. The mean BP at baseline was 140.7/81.4 mmHg. Throughout the follow-up period, the mean BP was 133.4/77.5 (95% CI, 132.7-134.1/76.9-78.2) mmHg in the standard group and 126.7/74.1 (95% CI, 126.0-127.4/73.5-74.8) mmHg in the intensive group. During a mean follow-up of 3.9 years, 78 first recurrent strokes occurred. Intensive treatment tended to reduce overall annual stroke recurrence (1.74% in intensive vs. 2.17% in standard; P = 0.351 by log-rank test) and did not change the risk of ischemic stroke (1.74% vs. 1.75%, P = 0.999) but markedly reduced the risk of hemorrhagic stroke (0.00% vs. 0.39%, P = 0.005). Beneficial effects of intensive BP control were observed for the risk of hemorrhagic stroke in patients with a history of ischemic stroke. The findings of this study indicate the benefit of intensive BP control for patients with a history of ischemic stroke at high risk of hemorrhagic stroke.

Background The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (Findings We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group. Interpretation Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Funding British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.

The Japanese hypertension guidelines report that essential hypertension is detected in 1–3% of upper elementary and high school students during blood pressure (BP) screenings. Hypertension in these age groups is an emerging public health concern mainly attributed to the rising rate of pediatric obesity. Considering the existence of BP tracking phenomenon, early preventive education and instruction are necessary, especially for male students with moderately elevated BP showing a tendency toward obesity, despite the low prevalence of hypertension in high school students. Students with a positive family history of hypertension and those born with low birth weight need the same measures. Lifestyle habits, such as increased alcohol intake, dramatically change once students begin university; thus, early education and instruction regarding the factors influencing BP are necessary. In particular, for male students with higher BP during high school, caution regarding increased body weight is required irrespective of their level of obesity. Young adults aged

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

BACKGROUND The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (

We compared three benidipine-based regimens—that is, benidipine plus angiotensin receptor blocker (ARB), β-blocker (BB) or thiazide—and found that the benidipine–BB combination was less beneficial in reducing the risk of stroke than the benidipine–thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (

Background: Lowering of blood pressure after stroke reduces the risk of recurrent stroke, but the optimum target blood pressure level is unknown. We evaluated the effects of intensive versus standard blood-pressure-lowering regimen on the rate of recurrent stroke in patients with recent stroke. Methods: This randomised open-label trial included eligible patients in Japan who had recent, CT- or MRI-defined symptomatic ischaemic or haemorrhagic stroke. Patients were recruited between October 2010 and December 2015, and were randomly assigned 1:1 to blood pressure control to less than 140/90 mmHg, standard treatment, or to levels of less than 120/80 mmHg, intensive treatment, according to a parallel design. The primary endpoint was stroke including ischaemic stroke and intracerebral haemorrhage. Analysis was done by intention to treat. Findings: The trial was stopped early because of cessation of funding after the enrolment of 1263 out of the planned 2000 patients. Of these patients, 630 in the standard-treatment group and 633 in the intensive-treatment group were followed up for a mean of 3.9 (SD 1.5) years. Mean age was 67 (SD 8.8) years. After 1 year, the mean blood pressure was 132.0/77.5 mmHg (95% CI 130.9-133.0/76.6-78.3) in the standard target group and 123.7/72.8 mmHg (95% CI 122.6-124.8/72.0-73.7) in the intensive target group. Ninety-one first recurrent strokes occurred. Non-significant rate reductions were seen for all cases of stroke (hazard ratio 0.73, 95% CI 0.49-1.11, p=0.145); however, when this finding was pooled with the results of prior trials of intensive blood pressure lowering for secondary stroke prevention, the pooled risk ratio favoured intensive blood pressure control (relative risk 0.78, 95% CI 0.64-0.96, p= 0.016). Interpretation: Intensive blood pressure lowering does not significantly reduce stroke recurrence. The non-significant findings might be attributable to insufficient statistical power due to early termination of the trial or the modest difference in blood pressure level between groups. Nevertheless, the updated meta-analysis including this trial supports the target blood pressure of less than 130/80 mmHg in the secondary prevention of stroke. Clinical Trial Number: This study was registered with ClinicalTrials.gov, number NCT01198496. Funding Statement: Merck and Co. Inc., Bristol-Myers Squibb Company, Towa Pharmaceutical Co., Ltd, and Omron Corporation. Declaration of Interests: KK reports grants and personal fees from Daiichi Sankyo, grants and personal fees from Bayer Inc., grants and personal fees from Takeda Pharmaceutical, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from Sumitomo Dainippon Pharma, grants and personal fees from Astellas Pharma, grants and personal fees from Sanofi, outside the submitted work; YY has nothing to disclose; HA reports personal fees from Bayer, personal fees from Daiichi Sankyo, personal fees from Fukuda Denshi, personal fees from Kyowa Kirin, personal fees from Takeda, outside the submitted work; TM has nothing to disclose; NS has nothing to disclose; TK has nothing to disclose; KM has nothing to disclose; KeKa has nothing to disclose; KM reports personal fees from Bayer Yakuhin, personal fees from Otsuka Pharmaceutical, personal fees from Boehringer-Ingelhaeim, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Mitsubishi Tanabe Pharma Cooperation, personal fees from Japan Stryker, personal fees from Kowa, personal fees from Nihon Medi-Physics Co., personal fees from BM from Bayer Yakuhin, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from Mochida Pharmaceutical, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Takeda Pharmaceutical, grants from Mitsubishi Tanabe Pharma, grants from Novartis Pharma, grants from Otsuka Pharmaceutical, grants from Pfizer Japan, grants from Shionogi & Co, grants from Teijin Pharma, outside the submitted work; YO reports grants and personal fees from Takeda Pharma, grants and personal fees from Daiichi-Sankyo, grants from Novartis Pharma, grants from Asterasu, personal fees from Dainippon-Sumitomo, personal fees from MSD, grants and personal fees from Bayer, grants and personal fees from Pfizer, grants and personal fees from Bohelinger, outside the submitted work; TK has nothing to disclose; YaOk has nothing to disclose; NT has nothing to disclose; GK has nothing to disclose; SaUm reports grants from Dainippon-Sumitomo, grants from Asteras, grants from Pfizer, grants from Nippon Boehringer Ingelheim, grants from Daiichi-Sankyo, grants from Takeda, personal fees from Nippon Boehringer Ingelheim, personal fees from Takeda, outside the submitted work; MM reports personal fees from Kowa Pharmaceutical Co Ltd, personal fees from Takeda Pharmaceutical Co Ltd, personal fees from Bayer Yakuhin, Ltd, personal fees from Sanofi KK, personal fees from Daiichi Sankyo Co0 Ltd, personal fees from Otsuka Pharmaceutical Co Ltd, personal fees from Astellas Pharma Inc, personal fees from Astra Zeneca KK, personal fees from Mochida Pharmaceutical Co, Ltd, personal fees from Sumitomo Dainippon Pharma Co Ltd, personal fees from Amgen Astellas BioPharma KK, personal fees from Esai Co, Ltd, personal fees from Pfizer Japan Inc, outside the submitted work; KS reports personal fees from Takeda, personal fees from Sumitomo Dainippon Pharma Co. Ltd., personal fees from MSD, personal fees from Astellas Pharma, personal fees from Boehringer-Ingelheim, personal fees from Bayer Yakuhin, outside the submitted work; SI reports personal fees from MSD, during the conduct of the study; grants and personal fees from Daiichi Sankyo, grants and personal fees from Takeda, grants and personal fees from Astellas, personal fees from Boehilinger-Ingerhaim, outside the submitted work; TS has nothing to disclose; KS reports personal fees from Dainippon-Sumitomo LTD, and Daiichi-Sankyo. Ethics Approval Statement: Participation required written informed consent, and approval was provided by the local ethics committees for human research.

Objective:The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial.Methods:Japanese hypertensive patients age

The cardiovascular effects of combined therapy with the angiotensin receptor blocker (olmesartan) and a dihydropyridine calcium channel blocker (CCB) or a diuretic were compared in high-risk elderly Japanese hypertensive patients by performing a randomized, open label, blinded-endpoint study of morbidity and mortality (the COLM study). Here we report the results obtained with respect to safety and tolerability. High-risk hypertensive patients aged 65-84 years were enrolled and were randomized to receive olmesartan combined with either a CCB (amlodipine or azelnidipine) or a low-dose diuretic for at least 3 years. The primary endpoint was a composite of fatal and non fatal cardiovascular events, whereas adverse events (AEs) and the percentage of patients who discontinued the allocated treatment were evaluated as secondary endpoints. A total of 5141 patients were randomized. Both combination regimens achieved a similar reduction of cardiovascular morbidity and mortality. The incidences of AEs, serious AEs, drug-related serious AEs and discontinuation due to serious AEs were lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group. Serum levels of uric acid and creatinine were significantly higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group. Olmesartan combined with a CCB was significantly superior to olmesartan plus a diuretic with regard to the frequency of AEs and discontinuation of treatment.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was a multicenter, randomized, three-arm comparative study (N=3293) undertaken to determine the optimal combination therapy, based on the occurrence of cardiovascular events in patients treated with an angiotensin II receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD) in addition to the calcium antagonist benidipine as baseline medication. This subanalysis was conducted to compare the efficacy of three combination therapies in a subset of 834 patients with chronic kidney disease (CKD) (287 patients treated with benidpine-ARB, 283 patients treated with benidipine-BB and 264 patients treated with benidipine-TD). The incidence of composite cardiovascular events as the primary end point did not differ among these three groups. The incidence of hard end points and cerebrovascular events among these groups did not differ either, although the incidence among all patients in the COPE trial was lower in the benidipine-TD group than in the benidipine-BB group. The incidence of new-onset diabetes mellitus was higher in the benidipine-TD group than in the benidipine-ARB group among patients with CKD. The estimated glomerular filtration rate (eGFR) was maintained even after 12 months of treatment in patients with a baseline eGFR

Our aim was to assess optimal on-treatment blood pressure (BP) at which cardiovascular disease (CVD) and all-cause mortality risks are minimized in Japanese older adults with isolated systolic hypertension. We used data from the VALISH study (Valsartan in Elderly Isolated Systolic Hypertension) that recruited older adults (n=3035; mean age, 76 years) with systolic BP (SBP) of ≥160 mm Hg and diastolic BP of Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00151229.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP

Although calcium antagonists elicit predominant dilation of afferent arterioles that might be associated with glomerular hypertension, there have been reported diverse observations demonstrating the effect of calcium antagonists on the progression of renal injury. The present study examined the effect of pranidipine (CAS 99522-79-9) on the renal microvascular tone in the isolated perfused hydronephrotic rat kidney, and the progression of renal insufficiency in subtotally nephrectomized spontaneously hypertensive rats. In the hydronephrotic kidney, angiotensin II caused marked constriction of both afferent and efferent arterioles. The subsequent addition of pranidipine (10 nmol/l, 100 nmol/l, 1 mumol/l) elicited dose-dependent afferent arteriolar dilation, with 97 +/- 3% reversal at 1 mumol/l. In contrast, efferent arterioles were resistant to pranidipine, with only 20 +/- 4% reversal at 1 mumol/l. In subtotally nephrectomized rats, 10-week treatment with pranidipine (3.0 mg/kg/day) markedly decreased blood pressure (from 270 +/- 6 to 158 +/- 8 mmHg) and improved renal histopathological changes, including glomerular and arteriolar sclerosis. Proteinuria was also less than than in the control rats (233 +/- 5 vs. 305 +/- 26 mg/day). Thus, although glomerular hypertension might develop as a consequence of preferential afferent arteriolar dilation, pranidipine actually improved the renal injury in subtotally nephrectomized SHR. These ostensibly discrepant observations could be attributed to the simultaneous reduction in blood pressure and the salutary actions of this agent mediated by non-hemodynamic mechanisms.

Caudal ventrolateral medulla (CVLM) neurons have important roles in the regulation of sympathetic nerve activity and blood pressure through their tonic inhibition of rostral ventrolateral medulla neurons. As few reports have demonstrated CVLM neuronal activity using the whole-cell patch-clamp technique, we attempted to find neurons in the CVLM that are depolarized by the stimulation of baroreceptors. To record the membrane potentials of the neurons in the CVLM, we developed a modified brainstem-spinal cord preparation that enabled us to change the pressure exerted on the aortic arch and carotid sinuses. We were able to identify neurons in the CVLM in which they were depolarized and the action potential (AP) frequency was increased upon baroreceptor stimulation. We referred to these neurons as baro-excited CVLM neurons. When these preparations were superfused with an angiotensin-II (Ang-II) solution, the frequency of the APs increased in 10 of the 14 baro-excited CVLM neurons. Superfusion with a low-Ca(2+), high-Mg(2+) solution abolished the APs in all seven baro-excited CVLM neurons, suggesting that the baro-excited CVLM neurons did not fire spontaneously. When the preparation was superfused with a low-Ca(2+) solution, 6 of the 7 baro-excited CVLM neurons did not respond to Ang-II superfusion. We for the first time found the baro-excited CVLM neurons, which depolarized pressure dependently but may not fire spontaneously. As Ang-II did not change the activity of the CVLM neurons during superfusion with a low-Ca(2+), high-Mg(2+) solution, the presynaptic neurons may be mandatory for the Ang-II-induced activation of postsynaptic baro-excited CVLM neurons.

BACKGROUND The impact of the metabolic syndrome (MS) on cardiovascular events in elderly subjects has not been clarified. We hypothesized that the impact differs between patients with and without strictly controlled blood pressure (BP) and also between early elderly (

In the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, comparable efficacy was noted between candesartan and amlodipine in the incidence of cardiovascular (CV) morbidity and mortality during 3.2 years of follow up. Candesartan suppressed new-onset diabetes more effectively than amlodipine. In this observational study, we investigated whether or not the efficacy of the two drugs is sustainable for another 3 years beyond the experimental period of the CASE-J trial. Of the 4728 high-risk hypertensive patients initially enrolled in the CASE-J trial, 2232 agreed to further follow up. The primary endpoint was a composite of CV morbidity and mortality. The distribution of demographic characteristics for the 2232 patients in the CASE-J extension was similar to that in the initial 4703 patients in the CASE-J trial. Both drugs controlled blood pressure well over the relatively long period of time. The incidence of CV events was 15.5/1000 patient years in the candesartan group and 16.3/1000 patient years in the amlodipine group (Hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.77-1.18; P=0.650). The incidence of new-onset diabetes was significantly lower in the candesartan group (9.5/1000 patient years) than in the amlodipine group (13.3/1000 patient years), representing a 29% risk reduction for new-onset diabetes (HR=0.71, 95% CI=0.51-1.00, P=0.0495). In conclusion, candesartan and amlodipine showed comparable efficacy against CV events beyond the experimental period of the CASE-J trial in high-risk hypertensive patients. In addition, the effects of candesartan on new-onset diabetes observed during the CASE-J trial were sustained in the CASE-J extension. The CASE-J extension, which covered a 3-year extension of follow-up from the original trial, corroborated the results of the CASE-J trial.

Background Although intention-to-treat analysis is a standard approach, additional supplemental analyses are often required to evaluate the biological relationship among interventions, intermediates, and outcomes. Therefore, we need to evaluate whether the effect of an intervention on a particular outcome is mediated by a hypothesized intermediate variable. Purpose To evaluate the size of the direct effect in the total effect, we applied the marginal structural model to estimate the average natural direct and indirect effects in a large-scale randomized controlled trial (RCT). Method The average natural direct effect is defined as the difference in the probability of a counterfactual outcome between the experimental and control arms, with the intermediate set to what it would have been, had the intervention been a control treatment. We considered two marginal structural models to estimate the average natural direct and indirect effects introduced by VanderWeele ( Epidemiology 2009) and applied them in a large-scale RCT – the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J trial) – that compared angiotensin receptor blockers and calcium-channel blockers in high-risk hypertensive patients. Results There were no strong blood pressure-independent or dependent effects; however, a systolic blood pressure reduction of about 1.9 mmHg suppressed all events. Compared to the blood pressure-independent effects of calcium channel blockers, those of angiotensin receptor blockers contributed positively to cardiovascular and cardiac events, but negatively to cerebrovascular events. Limitations There is a particular condition for estimating the average natural direct effect. It is impossible to check whether this condition is satisfied with the available data. Conclusion We estimated the average natural direct and indirect effects through the achieved systolic blood pressure in the CASE-J trial. This first application of estimating the average natural effects in an RCT can be useful for obtaining an in-depth understanding of the results and further development of similar interventions.

Steroidogenic factor-1 (SF-1) is a nuclear orphan receptor, which is essential for adrenal development and regulation of steroidogenic enzyme expression. SF-1 is posttranslationally modified by small ubiquitin-related modifier-1 (SUMO-1), thus mostly resulting in attenuation of transcription. We investigated the role of sumoylation enzymes, Ubc9 and protein inhibitors of activated STAT1 (PIAS1), in SF-1-mediated transcription of steroidogenic enzyme genes in the adrenal cortex. Coimmunoprecipitation assays showed that both Ubc9 and PIAS1 interacted with SF-1. Transient transfection assays in adrenocortical H295R cells showed Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of reporter constructs containing human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. Reduction of endogenous Ubc9 and PIAS1 by introducing corresponding small interfering RNA significantly reduced endogenous CYP17, CYP11A1, and CYP11B1 mRNA levels, indicating that they normally function as coactivators of SF-1. Wild type and sumoylation-inactive mutants of Ubc9 and PIAS1 can similarly enhance the SF-1-mediated transactivation of the CYP17 gene, indicating that the coactivation potency of Ubc9 and PIAS1 is independent of sumoylation activity. Chromatin immunoprecipitation assays demonstrated that SF-1, Ubc9, and PIAS1 were recruited to an endogenous CYP17 gene promoter in the context of chromatin in vivo. Immunohistochemistry and Western blotting showed that SF-1, Ubc9, and PIAS1 were expressed in the nuclei of the human adrenal cortex. In cortisol-producing adenomas, the expression pattern of SF-1 and Ubc9 were markedly increased, whereas that of PIAS1 was decreased compared with adjacent normal adrenals. These results showed the physiological roles of Ubc9 and PIAS1 as SF-1 coactivators beyond sumoylation enzymes in adrenocortical steroidogenesis and suggested their possible pathophysiological roles in human cortisol-producing adenomas.

Background: The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The aim of the present subanalysis was to evaluate the influence of coronary risk factors on coronary events in these patients as an observational study irrespective of allocated drugs. Methods and Results: The adjusted hazard ratios (HRs) of the association of baseline risk factors including gender, age, allocated drugs, body mass index, systolic/diastolic blood pressure (SBP/DBP), diabetes mellitus (DM), hyperlipidemia (HL), smoking, left ventricular hypertrophy, previous ischemic heart disease (IHD), previous cerebrovascular events, and chronic kidney disease (CKD) with coronary events in 4,703 patients who were enrolled in the CASE-J trial, were examined. The coronary events occurred in 83 patients, and were significantly associated with previous IHD, DM, male sex, CKD, and low DBP. Significant predictors were previous IHD (HR, 3.89), DM (HR, 3.10), male sex (HR, 1.81), CKD (HR, 1.60), and low DBP (HR, 1.36), respectively. In 4,107 patients without pre-vious IHD, DM (HR, 4.88), HL (HR, 2.67), and DBP (HR, 1.39) were significantly associated with the risk of coronary events, while male sex (HR, 3.03), CKD (HR, 2.44), and DM (HR, 2.15) were in 596 patients with previous IHD. Conclusions: DM is the important factor in both primary and secondary prevention of coronary events. Comprehensive risk management including surveillance of DM, CKD and HL is needed for preventing coronary events, in addition to blood pressure control. (Circ J 2011; 75: 2411-2416)

We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes.A total of 38 type 2 diabetic patients (22 men and 16 women; mean ± S.E.M. age 63.3 ± 1.0 years; duration of diabetes 9.6 ± 0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N(ɛ)-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean ± S.E.M. duration of diabetes 8.2 ± 0.7 years) as control (C group).The EP group showed significant suppression of deterioration of MCV (P.01) and minimum F-wave latency (P.01) in the tibial nerve and SCV (P.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (-0.18 ± 0.13 mU/ml in the EP group vs. +0.22 ± 0.09 mU/ml in the C group, P.05) after 1 year.Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.

This study evaluated the impact of renal function on cardiovascular outcomes in elderly hypertensive patients enrolled in the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive patients. The patients were randomly assigned to either a strict-treatment group (target systolic blood pressure (BP)

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (P =0.38). In summary, blood pressure targets of

In a previously reported randomized, double-blind, parallel-group study of the efficacy and tolerability of olmesartan medoxomil (OLM) and azelnidipine (AZL) combination therapy compared with monotherapy with each agent in Japanese patients with essential hypertension (the REZALT study), the use of a combination of OLM, an angiotensin II receptor blocker, plus AZL, a dihydropyridine calcium channel blocker, was associated with significantly greater reductions in office sitting blood pressure (BP) and 24-hour ambulatory BP compared with monotherapy with either agent, and was well tolerated.This article reports the results from an a priori planned analysis and post hoc analyses of the diurnal BP and pulse rate (PR) profiles of OLM/AZL versus monotherapy with either agent from the REZALT study.Male and female Japanese outpatients with essential hypertension were eligible if they met the following inclusion criteria: ageor = 20 years; systolic BP (SBP)or = 140 to180 mm Hg and diastolic BP (DBP)or = 90 to110 mm Hg; and 24-hour ambulatory SBP/DBPor = 135/or = 80 mm Hg. Patients were randomly assigned to receive OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM 20 mg, or AZL 16 mg, once daily for 12 weeks. The effectiveness of the treatments was assessed using 24-hour ambulatory BP monitoring (ABPM) and PR, analyzed by time period (BP and PR, 24 hours, daytime [7 AM-10 PM], nighttime [10 PM-7 AM], and early morning [6 AM-9 AM]; PR, morning [6 AM -11 AM]) and dipping status at baseline (dippers [(Daytime BP - Nighttime BP)/Daytime BPor = 10%] or nondippers [(Daytime BP - Nighttime BP)/Daytime BP10%]).A total of 867 patients were enrolled, and 862 randomized patients were included in the full analysis set (590 men, 272 women; mean age, 56.6 years). A total of 839 patients had assessable ABPM data (213, 211, 206, and 209 patients in the OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM, and AZL groups, respectively). No clinically significant between-group differences were observed in baseline demographic and clinical characteristics. Combination therapy was associated with significantly greater antihypertensive effects on 24-hour ABPM compared with either monotherapy in all of the time periods, as follows: SBP/DBP reductions with OLM/AZL 20/16 mg in the daytime, nighttime, and early morning were -22.6/-14.1, -21.2/-12.5, and -20.6/-11.9 mm Hg, respectively (all, P0.05 vs the other 3 treatment groups). The SBP/DBP reductions with OLM/AZL 10/8 mg (daytime, -18.2/-11.0 mm Hg; nighttime, -18.1/-10.0 mm Hg; and early morning, -15.6/-9.3 mm Hg) were also significantly greater than with OLM 20 mg (-11.8/-6.7, -12.8/-7.2, and -11.0/ -6.9 mm Hg, respectively; all, P0.01) and AZL 16 mg (-13.1/-7.8, -10.2/-5.5, and -9.9/-6.1 mm Hg; all, P0.001) in all of the time periods. The antihypertensive effects associated with OLM/AZL 10/8 mg or 20/16 mg were significantly greater than those with monotherapies regardless of dipping pattern at baseline (all, P0.05) in all of the time periods, with the exception of nighttime reduction with OLM/AZL 10/8 mg versus OLM in dippers. The numbers of patients who had any increase in BP were 12/213 (5.6%) with OLM/AZL 10/8 mg, 13/211 (6.2%) with OLM/AZL 20/16 mg, 35/206 (17.0%) with OLM, and 36/209 (17.2%) with AZL. The AZL-containing regimens were associated with reduced morning PR (mean [95% CI] changes from baseline to week 12: -1.5 beats/min [-2.5 to -0.4] with OLM/AZL 10/8 mg, -2.1 beats/min [-3.0 to -1.1] with OLM/AZL 20/16 mg, 0.4 beat/min [-0.5 to 1.3] with OLM, and -1.9 beats/min [-2.8 to -1.0] with AZL).In this study in Japanese patients with essential hypertension, the reductions in daytime, nighttime, and early-morning BP assessed using 24-hour ABPM were significantly greater with combination OLM/AZL than with either monotherapy, regardless of dipping pattern at baseline. Japan Pharmaceutical Information Center registration number: JapicCTI-060286.

Background/Aims: The role of matrix metalloproteinases (MMPs) in the pathogenesis of glomerular injury appears to be complex. To investigate the role of individual MMPs, we examined the course of Adriamycin-induced albuminuria and glomerulosclerosis in mice lacking either a gelatinase (MMP-9) or a collagenase (MMP-13). Methods: Adriamycin was administered to MMP-9 or MMP-13 knockout (KO) mice. Glomerular injury was assessed by the quantification of albuminuria, the glomerular injury score and type IV collagen immunostaining. Results: Treatment of mice with Adriamycin (18 mg/kg i.v.) resulted in marked albuminuria and glomerulosclerosis reaching a peak at 4–8 weeks. The albuminuria and glomerulosclerosis were significantly (p < 0.05) attenuated in both the MMP-9 KO and MMP-13 KO mice compared to controls. In contrast, treatment of wild-type mice with the broad-spectrum MMP inhibitor doxycycline did not have a beneficial effect on the albuminuria and glomerulosclerosis. Conclusion: These results support a role for both gelatinase (MMP-9) and collagenase (MMP-13) in the pathogenesis of glomerular injury in the Adriamycin-induced glomerulosclerosis model. MMP inhibitors with high specificity towards MMP-9 and/or MMP-13 may be potential future candidates to provide more effective therapies to inhibit the development of glomerulosclerosis.

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial assessed cardiovascular outcomes in high-risk hypertensive patients receiving either candesartan or amlodipine. The aim of this study was to examine the role of pre-existing diabetes or obesity on these outcomes as a sub-analysis of the trial. We examined the influence of pre-existing diabetes on cardiovascular morbidity and mortality using a multivariate Cox regression model. The cardiovascular morbidity and mortality of candesartan and amlodipine were compared between subgroups with or without pre-existing diabetes or by body mass index (BMI) category, and new-onset diabetes was compared by BMI category. Pre-existing diabetes greatly increased the cardiovascular mortality and morbidity, regardless of the allocated drugs. Furthermore, all-cause mortality was significantly higher with amlodipine than with candesartan among patients with BMI >or=27.5 kg m(-2) (adjusted hazard ratio (HR)=0.32; range=0.13-0.75; P=0.009). New-onset diabetes occurred significantly less frequently with candesartan than with amlodipine, with an adjusted HR of 0.66 (P=0.043). Furthermore, the increase in new-onset diabetes was dependent on BMI among patients receiving amlodipine, whereas no such dependency was observed for candesartan (interaction P=0.016). In conclusion, preexisting diabetes increased the risk of experiencing a cardiovascular event among high-risk Japanese hypertensive patients. Candesartan treatment may suppress all-cause death and reduce the incidence of new-onset diabetes in patients with obesity.

OBJECTIVE Hypertensive patients have an increased risk of developing diabetes. Accumulating evidence suggests a close relation between metabolic disturbance and increased arterial stiffness. Here, we examined the association between pulse pressure and the risk of new-onset diabetes in high-risk Japanese hypertensive patients. RESEARCH DESIGN AND METHODS The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial examined the effects of candesartan and amlodipine on the incidence of cardiovascular events in 4,728 high-risk Japanese hypertensive patients. In the present study, we analyzed the relationship between pulse pressure at baseline and new-onset diabetes in 2,685 patients without diabetes at baseline (male 1,471; mean age 63.7 years; mean BMI 24.8 kg/m2) as a subanalysis of the CASE-J trial. RESULTS During 3.3 ± 0.8 years of follow-up, 97 patients (3.6%) developed diabetes. In multiple Cox regression analysis, pulse pressure was an independent predictor for new-onset diabetes (hazard ratio [HR] per 1 SD increase 1.44 [95% CI 1.15–1.79]) as were male sex, BMI, and additional use of diuretics, whereas age and heart rate were not. Plots of HRs for new-onset diabetes considering both systolic and diastolic blood pressure (DBP) revealed that a higher pulse pressure with a lower DBP, indicating that the increased pulse pressure was largely due to increased arterial stiffness, was strongly associated with the risk of new-onset diabetes. CONCLUSIONS Pulse pressure is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. Increased arterial stiffness may be involved in the development of diabetes.

Background: In this subanalysis of the CASE-J, which was conducted to compare the effects of candesartan and amlodipine in Japanese high-risk hypertensive patients, the association of left ventricular hypertrophy (LVH) with renal function is clarified. Methods and Results: Patients were divided into 2 groups: 1,082 patients with LVH and 2,119 patients without LVH. The primary endpoint was the change in the estimated glomerular filtration rate (eGFR). The eGFRs were increased from 63.6 to 65.1 ml · min-1 · 1.73 m-2 in patients with LVH and from 63.6 to 68.5 ml · min-1 · 1.73 m-2 in those without LVH. The improvement in the eGFR was greater in patients without LVH than in those with LVH (P=0.004). In patients with chronic kidney disease (CKD) patients, the eGFR increased from 52.7 to 60.5 ml · min-1 · 1.73 m-2 in patients without LVH, but from 53.1 to 57.2 ml · min-1 · 1.73 m-2 in those with LVH (P

A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (

Objective To evaluate the associations of left ventricular hypertrophy (LVH) and its changes with the incidence of cardiovascular events and the time-course of serum creatinine (sCr) levels in high-risk hypertensive patients who participated in the Candesartan Antihypertensive Survival Evaluation in Japan trial. Methods We analysed data of 1447 patients who underwent echocardiography at enrolment as an observational study irrespective of allocation. According to the left ventricular mass index (LVMI) at the baseline, they were divided into two groups (without LVH, LVMI < 125g/m 2 ; n = 607 and with LVH, LVMI≥ 125 g/m 2 ; n = 840) and four categories on the basis of LVMI at the baseline and 1 year: absence of LVH (n = 285), development of LVH (n = 97), regression of LVH (n = 155), and persistence of LVH (n = 418). Results During 3.3 ± 0.8 years, cardiovascular events occurred in 20 (3.3%) patients without LVH and in 67 (8.0%) patients with LVH (hazard ratio: 2.58; 95% confidence interval: 1.54-4.33; P < 0.001 Among the four categories, absence of LVH was associated with lower risk of cardiovascular events than persistence of LVH (hazard ratio: 0.30; 95% confidence interval: 0.13-0.71; P= 0.006), but development or regression of LVH was not. Only in persistence of LVH did the sCr level significantly increase over time (baseline vs. 3 years; 0.92 vs. 1.02 mg/dl, P < 0.001). Adjusted sCr level of absence and regression of LVH at 3 years was significantly lower than that of persistence of LVH (0.89 and 0.90 vs. 0.97 mg/dl, P < 0.001, P= 0.002, respectively), but that of development of LVH was not. Conclusion Protection against LVH is associated with a reduced risk of cardiovascular events and may be related to the preservation of renal function in high-risk hypertensive patients.

The tumor necrosis factor (TNF)-alpha pathway has a key role in regulating insulin resistance. TNF receptor 2 (TNFR2) is an emerging candidate gene for insulin resistance in essential hypertension. We examined the association of insulin resistance and enhanced TNF pathway with severe hypertension and the association of a microsatellite polymorphism of the TNFR2 gene with severe hypertension. Male severe essential hypertensive patients (HT) with the onset before 60 years of age and with genetic predispositions to hypertension were consecutively enrolled at our outpatient department (N=92). Normotensive men (NT) over 50 years of age were randomly registered from the participants in the annual health check program (N=78). Patients were selected as HT and NT who met stringent criteria for systolic/diastolic blood pressure (SBP/DBP) levelsor=180 and/or 110 mm Hg and120/80 mm Hg, respectively. HT revealed significantly higher plasma insulin levels, C-reactive protein (CRP) and soluble fraction of TNFR2 concentrations (sTNFR2) than NT. A microsatellite polymorphism of the CA repeat in intron 4 of the TNFR2 gene was analyzed. The allele frequency of CA16 in HT differed significantly from that in NT (66/184 vs. 36/156, P=0.01 by chi(2) analysis). In HT, the CA16 carriers showed significantly higher SBP and plasma insulin levels and a higher tendency of sTNFR2 than did those without this allele. In NT, CA16 carriers revealed significantly higher sTNFR2 and CRP levels than did the CA16 non-carriers. These results suggest that the TNFR2 gene locus has a potential effect on developing severe hypertension through the augmented TNF pathway and insulin resistance.

Hypertension is a disease which affects over 26.4% of the world adult population, therefore novel approaches to the prevention and treatment of this disease need to be examined. Previous studies from our and other laboratories have shown that treatment of spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats with a renin-angiotensin system (RAS) inhibitor during the 'critical period' in hypertension development results in prevention of the later development of hypertension. In humans, Julius et al. reported similar findings in the landmark TROPHY study. Recently, we reported that 'pulse' treatment of SHR with high-dose angiotensin receptor blocker (ARB) is effective in causing sustained reduction of already established hypertension, even when the treatment was started after the 'critical period'. These results suggest the possibility that 'regression' of established hypertension may become feasible, and we have started a prospective, multicenter clinical study (STAR CAST study) to examine this possibility. In our animal studies, we found that treatment of rats during the 'critical period' with an ARB inhibits the development of renal arteriolar hypertrophy. Moreover, a high-dose angiotensin blocker caused a remarkable reversal of renal arteriolar hypertrophy in SHR, which was associated with changes in microvascular MMP expression. These results suggest that changes in the renal microvasculature may have an important role in the mechanisms of hypertension prevention and regression by ARB.

We examined the effects of candesartan and amlodipine on cardiovascular events in hypertensive patients with chronic kidney disease (CKD) using the data from the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial. CKD was defined as proteinuria and/or decreased GFR (

The COLM study is an investigator-initiated trial comparing the combination therapy using an angiotensin II receptor blocker (ARB), olmesartan, and a calcium channel blocker (CCB) with that using an ARB and a diuretic in high-risk elderly hypertensive patients. Here we describe the rationale and study design. Olmesartan was administered concomitantly with a long-acting dihydropyridine CCB (ARB/CCB group) or with a low-dose diuretic (ARB/diuretic group) to elderly hypertensive patients with a history of or risk factors for cardiovascular disease. Cardiovascular morbidity and mortality as a primary end point were compared between the two groups, with the target blood pressure (BP) being

Background: The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial compared the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The present study aimed to clarify the effect of cardiac complications on cardiovascular events in patients enrolled in CASE-J. Methods and Results: Cardiac complications were defined as left ventricular hypertrophy (LVH) and ischemic heart disease (IHD). The primary endpoint was a composite of sudden death, cerebrovascular, cardiac, renal and vascular events. The study group was divided into 2,030 and 2,673 patients with and without cardiac complications. During 3.2 follow-up years, cardiovascular events occurred for a rate of 13.6 per 1000 patient-years in patients without cardiac complications, and 23.1 per 1000 patient-years in patients with cardiac complications (adjusted hazard ratio (HR): 2.22; P

Genetic factors that induce essential hypertension have been examined using genome-wide linkage analyses. A quantitative trait locus (QTL) region that is closely linked to hypertension has been found on chromosome 1 in stroke-prone spontaneously hypertensive rats (SHRSPs). We used 2 congenic rats in which the blood pressure QTL on rat chromosome 1 was introgressed from SHRSP/Izm to Wistar-Kyoto (WKY)/Izm (WKYpch1.0) and from WKY/Izm to SHRSP/Izm (SHRSPwch1.0) rats by repeated backcrossing. Previous studies reported that the intermediate phenotype of this QTL for hypertension is characterized by the hyperactivity of the sympathetic nervous system in response to physiological and psychological stress. We performed intracellular patch-clamp recordings of rostral ventrolateral medulla (RVLM) neurons from WKY, WKYpch1.0, SHRSPwch1.0, and SHRSPs and compared the basal electrophysiological activities of RVLM neurons and the responses of these neurons to angiotensin II. The basal membrane potential of RVLM neurons from WKYpch1.0 was significantly “shallower” than that of the neurons from WKY. The depolarization of RVLM neurons from WKYpch1.0 in response to angiotensin II was significantly larger than that in neurons from WKY rats, whereas the depolarization of RVLM neurons from SHRSPwch1.0 was significantly smaller than that in neurons from SHRSPs. The response to angiotensin II of RVLM neurons from WKYpch1.0 and SHRSPs was sustained even after the blockade of all of the synaptic transmissions using tetrodotoxin. The QTL on rat chromosome 1 was primarily related to the postsynaptic response of RVLM bulbospinal neurons to brain angiotensin II, whereas both the QTL and other genomic regions influenced the basal activity of RVLM neurons.

The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.

Objective: Peroxisome proliferator–activated receptor (PPAR)-γ ligand, pioglitazone (PIO), is reported to induce edema especially in postmenopausal women. The aim of this study was to elucidate the mechanism for PIO-induced sodium retention and to discover the therapeutic strategy for the PIO-induced changes in renal sodium handling. Methods and Procedures: Zucker obese rats were ovariectomized and were given PIO for 8 weeks. Renal sodium excretion and renal expressions of several enzymes that generate natriuretic substances were examined. Results: Sodium excretion was decreased in ovariectomized (OVX) rats that were given PIO when compared with OVX rats that were not. Urinary nitrites/nitrates excretion was decreased in OVX rats, but was restored by PIO. The expressions of nitric oxide synthases (NOSs) and cyclooxygenases-1/2 (COX-1/2) were unaltered. Similarly, the expression of epithelial sodium channels (ENaC), identified as a PPAR-γ-regulated gene product, was unaffected. In contrast, the expression of cytochrome P450 4A (CYP4A) was increased in OVX rats, and was downregulated by PIO. Co-treatment of OVX rats with PIO and PPAR-α ligand, fenofibrate, a putative inducer of CYP4A, restored not only the impaired sodium excretion but also the downregulated CYP4A expression. Discussion: PIO-induced sodium retention is specific in female OVX rats. Ovariectomy decreases renal NO production, but upregulates renal CYP4A expression to compensate for renal sodium balance. In this setting, PIO downregulates CYP4A, leading to sodium retention. Furthermore, PPAR-α ligands can provide a novel strategy for preventing the PIO-induced sodium retention.

The Candesartan Antihypertensive Survival Evaluation in Japan Trial was designed to compare the long-term effects of the angiotensin II receptor blocker candesartan and the calcium channel blocker amlodipine on the incidence of cardiovascular events, represented as a composite of sudden death and cerebrovascular, cardiac, renal, and vascular events in high-risk Japanese hypertensive patients. We conducted a prospective, randomized, open-label study with blinded assessment of the end point in 4728 Japanese hypertensive patients (mean age: 63.8 years; mean body mass index: 24.6 kg/m 2 ). Patients were followed for an average of 3.2 years. Blood pressure was well controlled with both treatment-based regimens (systolic blood pressure/diastolic blood pressure: 136.1/77.3 mm Hg for candesartan-based regimens and 134.4/76.7 mm Hg for amlodipine-based regimens after 3 years). Primary cardiovascular events occurred in 134 patients with both the candesartan- and amlodipine-based regimens. The 2 treatment-based regimens produced no significant differences in cardiovascular morbidity or mortality in the high-risk Japanese hypertensive patients (hazard ratio: 1.01; 95% CI: 0.79 to 1.28; P =0.969). In each primary end point category, there was no significant difference between the 2 treatment-based regimens. New-onset diabetes occurred in fewer patients taking candesartan (8.7/1000 person-years) than in those taking amlodipine (13.6/1000 person-years), which resulted in a 36% relative risk reduction (hazard ratio: 0.64; 95% CI: 0.43 to 0.97; P =0.033). We disclosed that candesartan-based and amlodipine-based regimens produced no statistical differences in terms of the primary cardiovascular end point, whereas candesartan prevented new-onset diabetes more effectively than amlodipine.

To directly investigate whether a monosynaptic connection exists between neurons in the rostral ventrolateral medulla (RVLM) and sympathetic preganglionic neurons (SPNs), we used simultaneous extracellular recordings of RVLM neurons and whole-cell patch-clamp recordings of SPNs at the Th2 level and analyzed them by spike-triggered averaging. We averaged 200 sweeps of membrane potentials in SPN triggered by the spikes in the RVLM neuron. No clear postsynaptic potentials were detected in the averaged wave of SPNs before angiotensin II (Ang II) superfusion, whereas during superfusion with Ang II (6 micromol/L) on the medulla oblongata side alone excitatory postsynaptic potentials (EPSPs) were clearly found in the SPN of 3 out of 10 pairs at 40 +/- 1 ms after the averaged triggering spike in the RVLM neuron. We consider them to be monosynaptic EPSPs, because 1) the averaged EPSPs exhibited a sharp rise time, 2) the onset latency of the averaged EPSPs in the SPNs after the trigger spike in the RVLM was the same as the latency of the antidromic action potentials in the RVLM neurons in response to electrical stimulation of the SPNs, and 3) the amplitude of the averaged EPSPs was over 2 mV. In summary, combining simultaneous recording and spike-triggered averaging allowed us to demonstrate a monosynaptic excitatory connection between a single RVLM neuron and a single SPN in the thoracic spinal cord. Such connections provide the basis for the maintenance of sympathetic tone and the integrative reflex that relays through the RVLM. The results explain the mechanism by which Ang II in the RVLM area increases peripheral sympathetic activity and blood pressure.

As recommended by the guidelines such as JSH 2004, combination therapy with multiple agents is now being applied to many patients with hypertension. However, a pharmacoeconomic analysis of each therapy has not been fully undertaken in Japan, despite increasing societal interest. In this study, the cost-effectiveness of two calcium channel blockers, each coadministered with an angiotensin receptor blockade, was compared using data from the ADVANCE-Combi study. The ADVANCE-Combi study was a 16-week double-blind, randomized clinical trial to compare the efficacy and safety of two combination therapies (controlled-release nifedipine [nifedipine CR] plus valsartan vs. amlodipine plus valsartan) on blood pressure (BP) control in patients with moderate to severe essential hypertension. The incremental cost effectiveness of each cohort was compared from the perspective of insurers. The average total cost per patient was Japanese yen (JPY) 31,615 for the nifedipine CR treatment group and JPY 35,399 for the amlodipine treatment group (p < 0.001). The achievement rate of the target BP (SBP/DBP < 130/85 mmHg for patients aged under 60 years; SBP/DBP < 140/90 mmHg for those aged 60 years and over) was significantly higher in the nifedipine CR treatment group (61.2%) than in the amlodipine treatment group (34.6%) (p < 0.001), with no difference in the incidence of drug-related adverse events. Accordingly, the base case economic analysis demonstrated that the nifedipine CR treatment group was dominant (more efficacious and less costly) to the amlodipine treatment group. This result was supported by univariate and probabilistic sensitivity analyses. These results indicate that nifedipine CR-based combination therapy is superior to amlodipine-based combination therapy for the management of essential hypertension in the Japanese population.

To evaluate the clinical efficacy and safety of a new angiotensin II type 1 receptor blocker, pratosartan, in patients with mild-to-moderate essential hypertension, a multicenter, open-label study was conducted. A 2- to 4-week run-in period was followed by a 12-week core study with pratosartan monotherapy, or a combination of pratosartan with a calcium channel blocker (CCB) or diuretic. Patients took a daily dose of 40, 80, or 160 mg pratosartan, with titration at 4-week intervals. Patients who tolerated pratosartan at the end of a 12-week core study then participated in a 9-month follow-up period (i.e., long-term study). Responder rates by pratosartan were 82.1% in the monotherapy, 81.3% in the combination with CCB, and 60.0% in the combination with diuretic group at 12 weeks. Pratosartan was efficacious throughout the long-term study, without serious adverse effects. Pratosartan significantly decreased serum total cholesterol in patients with hypercholesterolemia and uric acid in patients with hyperuricemia. In conclusion, pratosartan is an effective and well tolerated antihypertensive drug, and may have beneficial effects on hypertensive patients with some metabolic disorders.

For hypertensive patients, it has been recommended that antihypertensive treatment strategies be chosen on the basis of the patients' conditions and age. In this sub-analysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, we aimed to compare the effects of candesartan and amlodipine on cardiovascular mortality and morbidity in Japanese elderly patients with high-risk hypertension and to determine their optimal target blood pressures (BPs). The effect of the two drugs on cardiovascular events was compared across different age subgroups (65, 65-74, and 75-84 years) by use of Cox regression analysis. We also evaluated the associations between the achieved BP and the incidence of cardiovascular events, irrespective of the allocated drugs in multiple Cox regression analyses. The incidence of cardiovascular events was independent of the assigned treatment for each of the age subgroups. For systolic BP (SBP), cardiovascular risk increased steeply when control of SBP was inadequate (higher than 140 mmHg) for patients younger than 65 years old and those between 65 and 74 years old. Patients aged 75 to 84 years old showed a significantly increased risk when their SBP wasor=150 mmHg. For diastolic BP (DBP), the risk significantly increased for the subgroup aged 75 to 84 years when the DBP wasor=85 mmHg. The present results show that candesartan and amlodipine are equally effective in Japanese elderly patients with high-risk hypertension. Moreover, it is important to control BP levels to less than 150/85 mmHg for patients 75-84 years old.

Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >or= 1.4 and P