Expression of (Pro)renin Receptor During Rapamycin-Induced Erythropoiesis in K562 Erythroleukemia Cells and Its Possible Dual Actions on Erythropoiesis.

(Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, is expressed in erythroblastic cells. (P)RR has multiple biological actions: prorenin activation, stimulation of the intracellular signaling including extracellular signal-regulated kinases, and functional complex formation with vacuolar H+-ATPase (v-ATPase). However, the functional implication of (P)RR in erythroblast cells has not been clarified. The aim of the present study was to clarify changes of (P)RR expression during erythropoiesis and a role of (P)RR in the heme synthesis. (P)RR expression was studied during rapamycin-induced erythropoiesis in a human erythroleukemia cell line, K562. Treatment with rapamycin (100 nM) for 48 hours significantly increased %number of hemoglobin-producing cells, γ-globin mRNA levels, erythroid specific 5-aminolevulinate synthase (ALAS2) mRNA levels, and heme content in K562 cells. Both (P)RR protein and mRNA levels increased about 1.4-fold during rapamycin-induced erythropoiesis. Suppression of (P)RR expression by (P)RR-specific small interference RNA increased ALAS2 mRNA levels about 1.6-fold in K562 cells, compared to control using scramble RNA, suggesting that (P)RR may down-regulate ALAS2 expression. By contrast, treatment with bafilomycin A1, an inhibitor of v-ATPase, decreased greatly % number of hemoglobin-producing cells and heme content in K562 cells, indicating that the v-ATPase function is essential for hemoglobinization and erythropoiesis. Treatment with bafilomycin A1 increased (P)RR protein and mRNA levels. In conclusion, we propose that (P)RR has dual actions on erythropoiesis: the promotion of erythropoiesis via v-ATPase function and the down-regulation of ALAS2 mRNA expression. Thus, (P)RR may contribute to the homeostatic control of erythropoiesis.

Water Deprivation Increases (Pro)renin Receptor Levels in the Kidney and Decreases Plasma Concentrations of Soluble (Pro)renin Receptor.

Water deprivation activates the renin-angiotensin system. We have hypothesized that the renal expression of (pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, could be changed under dehydration. Moreover, plasma levels of soluble (P)RR (s(P)RR) comprising of the extracellular domain of (P)RR may reflect the renal (P)RR expression. In the present study, we therefore aimed to clarify changes of plasma s(P)RR concentrations and kidney tissue (P)RR levels using rats with dehydration. Male Wister-Kyoto rats were divided into two groups; dehydrated (DH) rats deprived of water for 72 hours with free access to food, and control rats. Plasma s(P)RR concentrations measured by enzyme-linked immunosorbent assay were significantly lower in DH rats (6.94 ± 2.08 ng/mL, mean ± SD, n = 5) than in control (12.54 ± 2.00 ng/mL, n = 5) (p < 0.05). Western blot analysis confirmed lower expression levels of s(P)RR in plasma in DH rats than in control. By contrast, western blot analysis showed higher levels of full-length (P)RR and lower levels of furin (an enzyme responsible for generation of s(P)RR from full-length (P)RR) in the kidney tissues obtained from DH rats compared to control. There was no significant difference in the renal (P)RR mRNA levels between DH rats and control. These findings suggest that water deprivation may elevate the renal full-length (P)RR levels via reducing the expression of furin. Increased full-length (P)RR may contribute to the up-regulation of the renal renin-angiotensin system and the production of concentrated urine under dehydration.

A functional (pro)renin receptor is expressed in human lymphocytes and monocytes.

The renin-angiotensin system (RAS) is involved in inflammation. The signaling via the ANG II type 1 receptor in human lymphocytes and monocytes, which play key roles in pathophysiology of glomerulonephritis (GN), can enhance inflammation. However, the role of the (pro)renin receptor [(P)RR], a component of the RAS, in inflammatory reactions is unknown. We assessed whether (P)RR is expressed in human lymphocytes and monocytes by RT-PCR, Western blotting, flow cytometry, and immunohistochemistry, and whether (P)RR functions in inflammation. (P)RR mRNA and protein were expressed in human peripheral blood mononuclear cells (PBMCs). Flow cytometric analysis revealed high expression of (P)RR on monocytes. (P)RR was present on PBMCs, infiltrating lymphocytes, and macrophages around glomeruli with a crescent in anti-neutrophil cytoplasmic antibody (ANCA)-associated GN. Renin stimulation of PBMCs from healthy subjects in the presence of the ANG II type 1 receptor and ANG II type 2 receptor blockers induced ERK1/2 phosphorylation and release of IL-6 and expression of cyclooxygenase-2 (COX-2). The increases in cytokine release and COX-2 expression were inhibited in the presence of an ERK1/2 inhibitor. (P)RR knockdown by small interfering RNA in U937 cells, a human leukemic monocyte lymphoma cell line, significantly decreased ERK1/2 phosphorylation after renin stimulation. Thus (P)RR expressed in human inflammatory cells might contribute to inflammation in ANCA-associated GN.

Aldosterone-to-renin ratio and nocturnal blood pressure decline assessed by self-measurement of blood pressure at home: the Ohasama Study.

Based on ambulatory blood pressure (BP) monitoring, the aldosterone-to-renin ratio (ARR) has been reported to be associated with a diminished nocturnal decline in BP, generally referred to as a "non-dipping" pattern. The objective of this cross-sectional study was to investigate the association between ARR and the non-dipping pattern based on home BP measurements. This study included 177 participants≥55 years from the general population of Ohasama (mean age: 67.2 years; 74.6% women); no patient was receiving antihypertensive treatment. The median plasma renin activity (PRA), plasma aldosterone concentration (PAC) and ARR were 0.8 ng/mL/h, 8.1 ng/dL and 9.7 ng/dL per ng/mL/h, respectively. Each 1 SD increase in log-transformed (ln) ARR was significantly associated with the prevalence of the non-dipping pattern after adjustments for possible confounding factors including home morning systolic BP (odds ratio, 1.45; p=0.049). However, no significant associations of PRA or PAC with the non-dipping pattern were observed (p≥0.2). When participants were divided into four groups according to median levels of home morning and night-time systolic BPs, the group with a higher home morning systolic BP (≥128.4 mmHg) with a higher home night-time systolic BP (≥114.4 mmHg) had the greatest ARR levels (ANCOVA p=0.01). These results support the hypothesis that relative aldosterone excess may be related to a non-dipping pattern in a general population and suggest that a non-dipping pattern can be accurately observed by home BP measurements.

Pre-hypertension as a significant predictor of chronic kidney disease in a general population: the Ohasama Study.

BACKGROUND: Hypertension is associated with an increased risk of development of chronic kidney disease (CKD). However, it is unclear whether pre-hypertension is related to the incidence of CKD. METHODS: The incidence of CKD defined as positive proteinuria or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) was examined in 2150 inhabitants without pre-existing CKD from the general Japanese population. The association of blood pressure and CKD incidence was examined using a Cox regression model adjusted for age, sex, habitual smoking and drinking, obesity, history of cardiovascular disease, diabetes mellitus or hypercholesterolemia, eGFR at baseline, number of follow-up examinations and year of baseline examination. Participants were categorized according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. RESULTS: Participants were categorized into normotension (n = 586, 27.3 % ), pre-hypertension (n = 815, 37.9 % ), Stage 1 hypertension (n = 386, 18.0 % ) and Stage 2 hypertension (n = 363, 16.9 % ). During a mean follow-up of 6.5 years (14 023 person-years), 461 incidences of CKD were recorded. Compared to normotension, adjusted hazard ratios of CKD were significantly higher for pre-hypertension (1.49, P < 0.003), Stage 1 (1.83, P < 0.001) and Stage 2 (2.55, P < 0.001) hypertension. The population-attributable fraction of pre-hypertension (12.1 % ) was considered to be compatible to that of Stage 1 (8.6 % ) and Stage 2 (14.9 % ) hypertension. CONCLUSION: This was the first study to demonstrate that pre-hypertension was significantly associated with an increased risk of CKD and was one of the considerable causes of CKD in the general population.

Validation of the Parama-Tech PS-501 device for office blood pressure measurement according to the international protocol.

The PS-501 device (Parama-Tech, Fukuoka, Japan), an automated device for office blood pressure measurement based on the Korotkoff method and designed for professional use in clinical settings, was validated. Consecutive outpatients with hypertension and ≥30 years old at an outpatient hypertension clinic were recruited. According to the European Society of Hypertension protocol, 33 participants were included in the validation study (phase 1, n = 15; phase 2, n = 18). The cuff deflation rate can be selected manually from 2, 3, and 4 mm Hg/beat. The validation was performed with the device deflating at a rate of 2 mm Hg/beat. All blood pressure readings were measured on the left arm. The tested device passed all criteria for both systolic and diastolic blood pressure measurements. The mean (± standard deviation) differences in systolic and diastolic blood pressure between the tested device and the mean of observer readings were -1.9 ± 4.6 and -2.5 ± 2.9 mm Hg, respectively. The PS-501 device for office blood pressure measurement passed all the validation criteria of the European Society of Hypertension and can therefore be recommended for clinical use in an adult population.

Biotin ameliorates muscle cramps of hemodialysis patients: a prospective trial.

Patients with renal failure undergoing hemodialysis often have muscle cramps during and after the dialysis therapy. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied with severe pain, resulting in early termination of a HD session and inadequate dialysis. The etiology of the cramps is unknown and effective anti-cramp medicine is not available. We have hypothesized that water-soluble vitamins are deficient in HD patients. Accordingly, we administrated biotin to 14 patients who had frequent muscle cramps during HD sessions. Oral administration of 1 mg/day biotin promptly reduced the onset and the severity of cramps in 12 patients both during and after HD. Then, the plasma biotin levels were measured by an enzyme-linked immunosorbent assay method (ELISA) in HD patients, including 14 patients with cramps and 13 patients without cramps, and 11 healthy volunteers. Plasma biotin levels were elevated in 27 HD patients at baseline compared with healthy volunteers [451 (377 - 649) vs. 224 (148 - 308) ng/l, median (lower-upper quartiles); p < 0.0001]. Unexpectedly, among the 14 cramp patients, the biotin levels were significantly higher in biotin-ineffective 7 patients than biotin-effective 7 patients [1,064 (710 - 1,187) vs. 445 (359 - 476) ng/l; p < 0.001]. Thus, the biotins measured by ELISA may consist of not only intact biotin but also its metabolites that do not function as a vitamin. In conclusion, biotin administration is one choice to relieve HD patients from muscle cramps regardless of their elevated plasma biotin levels.

Associated factors of home versus ambulatory heart rate variability in the general population: the Ohasama study.

We previously demonstrated that heart rate (HR) variability obtained by daytime ambulatory monitoring and that of daily home measurement associated differently with cardiovascular mortality risk; cardiovascular mortality was linked with decreased daytime ambulatory HR variability and increased day-by-day home HR variability. The aim of this study was to identify factors contributing to each variability, clarifying possible reasons for their different predictive values. We obtained daytime ambulatory HR and home HR in 538 individuals of a general Japanese population aged ≥55 years. Daytime ambulatory HR variability and day-by-day home HR variability were estimated as a standard deviation measured every 30 min by daytime ambulatory monitoring and day-by-day home measurements once in the morning for 4 weeks, respectively. There was only weak correlation between daytime ambulatory HR variability and day-by-day home HR variability (r = 0.08∼0.14). In a multiple regression model, daytime ambulatory HR variability was associated with daytime ambulatory HR (P < 0.0001), daytime ambulatory blood pressure (BP) variability (P < 0.0001), and male sex (P = 0.003), while negatively associated with daytime ambulatory systolic blood pressure (SBP) (P < 0.0001) and smoking (P = 0.038). Meanwhile, day-by-day home HR variability was positively associated with home HR (P < 0.0001), day-by-day home BP variability (P < 0.0001), and male sex (P = 0.018). Associated factors of daytime ambulatory HR variability and day-by-day home HR variability were different. Our findings suggest that HR variabilities by different intervals of measurements might be mediated by different mechanisms.

Self-monitoring of ambulatory blood pressure by the Microlife WatchBP O3--an application test.

Ambulatory blood pressure monitoring (ABPM) is not widely used in clinical practice, because the measuring procedure is complex and the devices are expensive and need to be fitted by skilled medical technologists. The Microlife WatchBP O3 (Microlife AG, Widnau, Switzerland), which was developed for self blood pressure monitoring at home and adapted for ABPM, is highly affordable for an ABPM device and easy to manipulate. We performed an application test of the WatchBP O3 to confirm reliability of the device. Thirty-seven volunteer participants (age 30.4 ± 13.5 y) underwent blood pressure (BP) measurements every 30 min for 24 h, and were asked to complete a questionnaire about the user-friendliness and acceptability of the device. The participants were asked to attach the device and to detach it the next morning by themselves. The quality of recordings was assessed in terms of percentage of valid readings. The mean number of 24-h BP readings per participant was 46.6 ± 5.3. The percentage of valid readings was 90%, which was similar to that reported for traditional ambulatory devices. Eighty-six percent of participants found it is "easy" or "very easy" to attach the device by themselves. The WatchBP O3, which is easy to manipulate, may be convenient and acceptable for users. The percentage of valid readings is similar to that reported previously. A new era of self-monitoring of ambulatory BP is anticipated in the near future.

Individual assessment of inherent arterial stiffness using nomogram and pulse wave velocity index: the Ohasama study.

We measured the brachial-ankle pulse wave velocity (baPWV) in 491 normotensives and determined the "PWV index" (measured baPWV-theoretical baPWV) in 491 normotensives and 83 controlled hypertensives. Linear regression analysis revealed that the theoretical baPWV (cm/sec) was 0.21 × age(2) (years(2))-13.73 × age (years) + 0.05 × mean arterial pressure(2) (mmHg(2)) + 3.95 × heart rate (bpm) + 36.49 × gender (1 male; 0 female) + 733 (R(2) = 0.53). The calculated PWV index was significantly higher in 13 smokers than 70 nonsmokers among controlled hypertensives. The calculated PWV index might provide more precise information about inherent arterial stiffness.

Expression of adrenomedullin 2/intermedin, a possible reno-protective peptide, is decreased in the kidneys of rats with hypertension or renal failure.

Adrenomedullin 2/intermedin (AM2/IMD) is a potent vasodilator peptide with organ-protective effects and is abundantly expressed in the kidney. We examined the expression of AM2/IMD in the kidneys of rats with hypertension or chronic renal impairment using quantitative RT-PCR, radioimmunoassay, and immunohistochemistry. Kidneys of 8-wk-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were dissected into inner medulla, outer medulla, cortex, and glomerulus fractions. A rat renal impairment model was prepared by 5/6 nephrectomy in WKY rats. AM2/IMD mRNA levels were the highest in the cortex among four renal portions, and significantly lower in SHR than WKY rats in all renal portions. In the remnant kidneys of 5/6 nephrectomized rats, AM2/IMD mRNA levels were significantly decreased on days 3 and 56, whereas mRNA levels of calcitonin receptor-like receptor, receptor activity-modifying proteins-1 and -2, which form receptor for AM and AM2/IMD, were increased, compared with that in sham-operated rats. AM mRNA levels were decreased on day 3, but increased on day 56, after nephrectomy. Decreased immunoreactive AM2/IMD levels in the remnant kidneys of 5/6 nephrectomized rats on day 56 were confirmed by radioimmunoassay. The renal tubules were immunostained with anti-AM2/IMD antibody, with a decreased AM2/IMD immunostaining found in proximal tubular cells of 5/6 nephrectomized rats compared with sham-operated rats. In conclusion, intrarenal AM2/IMD expression is decreased in SHR and 5/6 nephrectomized rats. Given the organ-protective effects of AM2/IMD, the downregulation of AM2/IMD as an endogenous regulatory peptide may have a role in the progression of renal impairment.

Association of kidney dysfunction with silent lacunar infarcts and white matter hyperintensity in the general population: the Ohasama study.

BACKGROUND: No previous study has investigated the association of kidney dysfunction with silent lacunar infarcts and white-matter hyperintensity (WMH) independent of ambulatory blood pressure (BP). METHODS: A cross-sectional study involving 1,008 participants (mean age 66 years) from a general population of Ohasama, Japan, was conducted. Calculated creatinine clearance (CCr) was estimated using the Cockcroft-Gault equation. In continuous and categorical analyses, the association between CCr and the prevalence of silent lacunar infarcts and WMH was investigated. Silent lacunar infarcts and WMH were detected on MRI. Multiple logistic regression analysis adjusted for 24-hour ambulatory BP, sex, age, body mass index, smoking and drinking status, antihypertensive medication, and histories of hypercholesterolemia, diabetes mellitus and heart disease was performed. RESULTS: On univariate analysis, decreased CCr (continuous variable) and CCr <60 ml/min/1.73 m(2) (categorical variable) were significantly associated with lacunar infarcts and WMH. After adjustment, each 1-standard-deviation decrease in CCr (odds ratio = 1.22; p = 0.036) and CCr <60 ml/min/1.73 m(2) (odds ratio = 1.68; p = 0.007) was significantly associated with a high prevalence of lacunar infarcts. Even when 24-hour ambulatory BP was within the normal range (<130/80 mm Hg), CCr <60 ml/min/1.73 m(2) was associated with a high prevalence of lacunar infarcts (odds ratio = 1.62; p = 0.047). CCr <60 ml/min/1.73 m(2) and 24-hour ambulatory BP had additive effects on lacunar infarcts. After the same adjustment, the association between CCr and WMH was not significant. CONCLUSIONS: CCr is closely associated with lacunar infarcts, suggesting that kidney dysfunction in the elderly is an independent risk factor or predictor for silent lacunar infarcts.

Validation of the FM-800 ambulatory blood pressure monitor according to the Association for the Advancement of Medical Instrumentation criteria and the International Protocol.

To validate the FM-800 device (Fukuda Denshi Co., Ltd., Tokyo, Japan) for ambulatory blood pressure monitoring (ABPM), this validation study was performed based on the European Society of Hypertension (ESH) protocol and the Association for the Advancement of Medical Instrumentation (AAMI) criteria. Thirty-three participants were included (15 in phase 1 and an additional 18 in phase 2) in the ESH protocol. The device was tested on 85 participants according to the AAMI criteria, which require a mean device-observers discrepancy within 5 ± 8 mmHg. The tested device passed all the criteria for both systolic blood pressure (SBP) and diastolic blood pressure (DBP), and for the Korotkoff and oscillometric methods according to the ESH protocol. The test device also fulfilled the AAMI accuracy criteria for the 85 participants; the mean ± SD of the SBP/DBP differences between the tested device and the mean of the observer readings were -1.1 ± 4.2/-0.8 ± 4.2 mmHg for the Korotkoff method and 2.3 ± 3.9/-2.3 ± 3.9 mmHg for the oscillometric method. The FM-800 device for ABPM passed all the validation criteria of the ESH and AAMI and can, therefore, be recommended for clinical use in an adult population.

[Cost effectiveness of hypertension treatment based on the measurement of ambulatory blood pressure].

In recent years soaring medical costs have become a major social problem in developed countries. Ambulatory blood pressure (ABP) measurements have a stronger predictive power for cardiovascular events than clinic blood pressure (CBP) measurements. Therefore the introduction of ABP measurement for the diagnosis and treatment of hypertension should lead to a decrease in medical expenditure. This study presents calculations of the cost saving and life years associated with changing from CBP to ABP measurement as diagnostic tool. We constructed a Markov model using data from the Ohasama study and a Japanese national database. Study population was 7.042 million individuals aged 40 years and above living in Japan. The introduction of ABP for hypertension would result in a reduction of about 9.48 trillion yen per 10 years. We conducted a sensitivity analysis and found that the introduction of ABP was associated with at least a cost reduction of 47500 billion yen. But it did not provide significant extension of average life years. However the introduction of ABP for hypertension treatment would be a very effective method in perspective of public health because it reduced about 59600 individuals of stroke and about 18900 individuals of death. Given its cost-effectiveness, extensive application of ABP measurement in clinical practice is expected.

High Salt Intake-Increased (Pro)renin Receptor Expression Is Exaggerated in the Kidney of Dahl Salt-Sensitive Rats.

The (P)RR ([pro]renin receptor) was identified as a new component of the renin-angiotensin system. We previously reported that high salt (HS) intake increased the (P)RR expression in several nephron segments of Sprague-Dawley rats. Other studies reported HS intake increased the XO (xanthine oxidase) activity and an MR (mineralocorticoid receptor) antagonist inhibited HS intake-increased (P)RR expression in the kidneys of Dahl salt-sensitive (DS) rats. The present study examined the effects of HS intake on (P)RR expression in the kidney of DS rats. Male DS rats were fed a normal salt diet or an HS diet for 4 weeks. Some of the rats fed on the HS diet were treated with the XO inhibitor, febuxostat, and the MR antagonist, spironolactone. Immunoblot and immunohistochemical analyses showed that HS intake increased (P)RR expression in the renal cortex by 22.6-fold, the proximal tubules by 4.9-fold and the distal tubules, respectively. Both febuxostat and spironolactone inhibited HS intake-increased (P)RR expression in the renal cortex. Febuxostat inhibited HS intake-increased (P)RR expression in the proximal tubules, whereas spironolactone inhibited HS intake-increased (P)RR expression in the distal tubules. Additionally, deoxycorticosterone acetate increased (P)RR expression in the renal cortex and distal tubules but not in the proximal tubules of DS rats fed the normal salt diet. These results indicate that HS intake greatly increases (P)RR expression in the renal cortex of DS rats. The mechanisms of HS intake-increased (P)RR expression may work in an XO-dependent manner in the proximal tubules and an MR-dependent manner in the distal tubules.

Stroke risk of blood pressure indices determined by home blood pressure measurement: the Ohasama study.

BACKGROUND AND PURPOSE: The purpose of this prospective cohort study was to investigate associations between stroke and blood pressure (BP) indices (systolic BP [SBP], diastolic BP [DBP], mean BP, and pulse pressure [PP]) determined by home BP measurement. METHODS: Associations between stroke and BP indices were examined in a rural Japanese population. Home BP data of 2369 subjects (40% men) > or =35 years of age (mean, 59 years) without a history of stroke were obtained. Associations between stroke and each index were determined using Cox proportional hazards regression and the likelihood ratio (LR) test. RESULTS: During follow-up (mean, 11.7 years), 238 strokes occurred. The LR test showed that SBP and mean BP were significantly more strongly associated with total and ischemic stroke than DBP and PP (LR chi2 > or =9.3, P<0.01 for SBP/mean BP, LR chi2 < or =3.8, P> or =0.05 for DBP/PP). SBP tended to be more strongly associated with total/ischemic stroke than mean BP (LR chi2=3.8, P=0.05 for SBP, LR chi2 < or =0.2, P>0.6 for mean BP). PP tended to be slightly more strongly associated with ischemic stroke than DBP (LR chi2=7.5, P<0.01 for DBP, LR chi(2)=9.3, P<0.01 for PP), whereas DBP was significantly more strongly associated with hemorrhagic stroke than PP (LR chi2=9.2, P<0.01 for DBP, LR chi2=2.5, P=0.01 for PP). CONCLUSIONS: PP obtained from home BP measurements was weakly associated with stroke, whereas SBP showed the strongest association. Additionally, DBP and PP may be associated with different stroke types.

Increased expression of urotensin II-related peptide and its receptor in kidney with hypertension or renal failure.

Urotensin II-related peptide (URP) is a novel vasoactive peptide that shares urotensin II receptor (UT) with urotensin II. In order to clarify possible changes of URP expression in hypertension and chronic renal failure (CRF), the expressions of URP and UT were studied by quantitative RT-PCR and immunohistochemistry in kidneys obtained from spontaneous hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and WKY with CRF due to 5/6 nephrectomy. Expression levels of URP mRNA and UT mRNA were significantly higher in the kidneys obtained from SHR compared with age-matched WKY (at 5-16 and 16 weeks old, respectively). A dissection study of the kidney into three portions (inner medulla, outer medulla and cortex) showed that the expression levels of URP mRNA and UT mRNA were highest in the inner medulla and the outer medulla, respectively, in both SHR and WKY. The expression levels of URP and UT mRNAs were greatly elevated in the remnant kidneys of CRF rats at day 56 after nephrectomy, compared with sham-operated rats (about 6.5- and 11.9-fold, respectively). Immunohistochemistry showed that URP immunostaining was found mainly in the renal tubules, vascular smooth muscle cells and vascular endothelial cells. UT immunoreactivity was localized in the renal tubules and vascular endothelial cells. These findings suggest that the expressions of URP and UT mRNAs in the kidney are enhanced in hypertension and CRF, and that URP and its receptor have important pathophysiological roles in these diseases.

Cost-effectiveness of the introduction of home blood pressure measurement in patients with office hypertension.

OBJECTIVE: Cost-effectiveness of hypertension treatment is an important social and medical issue in Western as well as in Eastern countries, including Japan. Home blood pressure (HBP) measurements have a stronger predictive power for cardiovascular events than casual clinic blood pressure (CBP) measurements. Therefore, the introduction of HBP measurement for the diagnosis and treatment of hypertension should lead to a decrease in medical expenditure. This study presents calculations of the cost savings likely to take place when HBP is implemented for newly detected hypertensive subjects in Japan. DESIGN AND METHODS: We estimate the cost savings from the perspective of a Japanese healthcare system. To estimate the costs associated with changing from CBP to HBP measurement as the diagnostic tool, we constructed a simulation model using data from the Ohasama study. These calculations are based on current estimates for cost of treatment, prevalence of white-coat hypertension at baseline, and varying the incidence of new hypertension after the initial screening. RESULTS: When HBP measurement is not incorporated into the diagnostic process, the medical cost is estimated at US$10.89 million per 1000 subjects per 5 years. When HBP measurement is incorporated, the medical cost is estimated at US$9.33 million per 1000 subjects per 5 years. The reductions in medical costs vary from US$674,000 to US$2.51 million per 1000 subjects per 5 years for treatment of hypertension, when sensitivity analysis is performed. CONCLUSIONS: The introduction of HBP measurement for the treatment of hypertension is very useful for reducing medical costs.

Predictive value of ambulatory heart rate in the Japanese general population: the Ohasama study.

BACKGROUND: Resting heart rate can predict cardiovascular disease mortality or all-cause mortality. Because of the effect of the alert reaction, heart rates measured out-of-office should have better predictive power than those obtained at clinics. However, only a few studies have described the relationship between heart rate measured by ambulatory blood pressure monitoring devices and cardiovascular disease prediction. METHODS: We studied 1444 individuals from the Japanese general population who did not have a history of cardiovascular diseases including arrhythmia. We used multiple adjusted Cox proportional hazards to calculate the mortality risk of daytime heart rate, night-time heart rate, and the day-night heart rate dip ratio [day-night heart rate dip ratio = (daytime heart rate--night-time heart rate)/daytime heart rate x 100]. RESULTS: After 12 years of follow-up, 101, 195, and 296 participants died due to cardiovascular diseases, noncardiovascular diseases, and all causes, respectively. As shown by others, neither daytime nor night-time heart rate predicted cardiovascular disease mortality, whereas both predicted noncardiovascular disease mortality. The day-night heart rate dip ratio was significantly related to all-cause mortality. When night-time heart rate and day-night heart rate dip ratio were simultaneously included into the same Cox model, only night-time heart rate significantly and independently predicted all-cause mortality (relative hazard per 10 bpm increase = 1.29, 95% confidence interval, 1.07-1.54). CONCLUSION: Night-time heart rate value seems to have the most important predictor of all-cause mortality among ambulatory heart rate parameters in this population.

Increased expression of adrenomedullin 2/intermedin in rat hearts with congestive heart failure.

Adrenomedullin 2/intermedin (AM2/IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. To investigate the pathophysiological role of AM2/IMD in heart failure, we examined the expression of AM2/IMD, adrenomedullin (AM) and receptor complex components (calcitonin receptor-like receptor, three types of receptor activity-modifying proteins) by quantitative RT-PCR and immunohistochemistry in the hearts and kidneys of rats with congestive heart failure (CHF). Significantly increased levels of AM2/IMD mRNA were found in the atrium, right ventricle, non-infarcted part of the left ventricle and the infarcted part of the left ventricle of CHF rats, compared with sham operated rats (about 2.8-fold, 1.7-fold, 1.7-fold and 2.5-fold, respectively). Expression levels of mRNA encoding AM and the receptor complex components were also increased in the hearts of CHF rats. In a separate experiment, AM2/IMD mRNA levels in the heart did not differ between Wistar-Kyoto and spontaneously hypertensive rats. In both sham operated and CHF rats, the myocardium was diffusely immunostained with AM2/IMD. The fibrotic infarcted layer was not immunostained with AM2/IMD but was surrounded by positively immunostained myocardial layers. These findings suggest that the expression of AM2/IMD is enhanced in the failing heart, and AM2/IMD has a certain pathophysiological role in heart failure.