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Purposes: Central blood pressure is a stronger predictor of cardiovascular prognosis rather than brachial blood pressure. The reflection wave reaches the abdominal aorta sooner than ascending aorta. Thus, the contribution of central pulse pressure (cPP) to renal events may differ from that of cardiovascular events., Methods: The subanalysis of the ABC-J II study was performed. Subjects were 3434 treated hypertensive patients with a mean follow-up of 4.7 years. Left ventricular hypertrophy, an index of cardiovascular risk, correlated with cPP better than central systolic blood pressure in this cohort. The contribution of brachial pulse pressure (bPP) and cPP to cardiovascular and renal events was analysed., Results: Cox proportional-hazard analysis revealed that sex ( p  < 0.001), height ( p  < 0.05), history of cardiovascular diseases ( p  < 0.001), number of antihypertensive drugs ( p  < 0.05), and cPP ( p  < 0.05) contributed to cardiovascular events. However, Cox proportional-hazard analysis disclosed that baseline serum creatinine ( p  < 0.001) and bPP ( p  < 0.05) predicted renal events. After adjusting for the history of cardiovascular diseases, Cox regression demonstrated only sex as a significant predictor of cardiovascular events. After adjusting for baseline serum creatinine, no parameters were shown to predict renal events., Conclusions: The present findings support our previous data that the absence of cardiovascular or renal diseases is an important determinant for event-free survival, and suggest that cPP and bPP contribute to cardiovascular and renal events in treated hypertensive patients.

In this study, we developed an evaluation method using image analysis for reaching tasks. Using this method, we studied forearm function during the reaching task in rats that received a unilateral injection of 6-OHDA into the striatum. The success ratio of the reaching task reduced to 40.5% seven days after the injection. In addition, significant changes were observed in the pronation angle of the forearm, posture control, and targeting (i.e., the distance between all fingertips and the center of the target pellet). Thus, unilateral injection of 6-OHDA reduces dopaminergic function in the brain and causes deterioration of forearm function and posture control in the reaching task.

The rat reaching task is one of the best paradigms from behavioral study of upper limb movements. Rats are trained to reach and grab a pellet by extending their hand through a vertical slit. A few conventional imaging systems specific for the rat reaching task are commercially available with a high installation cost. Based on image analysis of video recordings obtained during the reaching task, we, herewith, developed a new, low-cost laboratory system that can be used for the quantitative analysis of ten basic forearm movements, in contrast to subjective assessments used in previous studies. We quantified images of the pronated and supinated palm and the accuracy and speed of reaching the target. Applying this newly developed method, we compared the forearm movements during the reaching task before and after a massive anatomical lesion of the sensorimotor cortex performed by tissue aspiration. We also wanted to investigate the recovery of upper limb function possibly induced by repeating the task for a relatively short term of a few weeks. In the experiment, 7 injured groups and 3 control groups were used. We found characteristic abnormalities of the forearm movements and a significant recovery in the success rate of grasping the target pellet. The present results demonstrate that our method is straightforward for the quantitative evaluation of forearm movements during the reaching task primarily controlled by the sensorimotor cortex., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Background: In April 2015, five types of phosphate binders (PBs) were available by prescription in Japan, namely calcium carbonate, sevelamer hydrochloride, lanthanum carbonate, bixalomer, and ferric citrate hydrate (FeC). FeC reduces serum phosphorus levels and increases the body's iron stores. However, it is unclear whether FeC lowers serum phosphorus relative to other agents in a regional practical setting., Methods: We performed a retrospective observational cohort study of regional hemodialysis surveillance in the western Saitama area of Japan, which included 1374 hemodialysis patients enrolled from 32 satellite dialysis units. The clinical data and prescribing information were retrospectively collected and analyzed. The difference in serum phosphorus among the groups administered five types of PBs (new or additional) from April to September 2015 was the primary outcome., Results: As of April 2015, the median values of serum phosphorus, corrected calcium, and intact parathyroid hormone were 5.4 mg/dL, 9.1 mg/dL, and 147 pg/dL, respectively (N = 1374). Unexpectedly, with an increase in the number of PBs administered, serum phosphorous levels increased (p < 0.001). The significant changes in the serum phosphorus and hemoglobin levels were associated with the prescription of FeC but not with that of the other PBs., Conclusions: This regional survey suggests that serum phosphorus is well managed and that FeC has the potential to reduce the serum phosphorus level relative to other PBs and to ameliorates anemia.

The long-term prognosis of patients with postoperative acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) after cardiovascular surgery is unclear. We aimed to investigate long-term renal outcomes and survival in these patients to determine the risk factors for negative outcomes. Long-term prognosis was examined in 144 hospital survivors. All patients were independent and on renal replacement therapy at hospital discharge. The median age at operation was 72.0 years, and the median pre-operative estimated glomerular filtration rate (eGFR) was 39.5 mL/min/1.73 m2. The median follow-up duration was 1075 days. The endpoints were death, chronic maintenance dialysis dependence, and a composite of death and chronic dialysis. Predictors for death and dialysis were evaluated using Fine and Gray's competing risk analysis. The cumulative incidence of death was 34.9%, and the chronic dialysis rate was 13.3% during the observation period. In the multivariate proportional hazards analysis, eGFR <30 mL/min/1.73 m2 at discharge was associated with the composite endpoint of death and dialysis [hazard ratio (HR), 2.1; 95% confidence interval (CI), 1.1-3.8; P = 0.02]. Hypertension (HR 8.7, 95% CI, 2.2-35.4; P = 0.002) and eGFR <30 mL/min/1.73 m2 at discharge (HR 26.4, 95% CI, 2.6-267.1; P = 0.006) were associated with dialysis. Advanced age (≥75 years) was predictive of death. Patients with severe CRRT-requiring AKI after cardiovascular surgery have increased risks of chronic dialysis and death. Patients with eGFR <30 mL/min/1.73 m2 at discharge should be monitored especially carefully by nephrologists due to the risk of chronic dialysis and death., Competing Interests: The authors have declared that no competing interests exist.

Objective: This simulation study attempted to infer the systolic blood pressure (SBP) levels at which subjects with hypertension, health nurses, and primary physicians should switch their preference of their treatment policies from lifestyle modifications to antihypertensive medications in virtual Japanese sample populations. Methods: We assumed that SBP levels were normally distributed and that the incidence rate of cardiovascular disease (IR CVD , events/year) increased exponentially according to SBP. The total IR CVD was calculated by the definite integral for the product of the distribution of SBP multiplied by IR CVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. We deduced the hypothetical SBP levels by solving differential equations of ∆(IR CVD )/ ∆(SBP) = 0 using numerical analysis. Results: In the realistic situations where the subjects were not affirmative to antihypertensive medications, the inferred SBP level to switch from lifestyle modifications to antihypertensive medications should be around 150 mmHg. If the subjects are affirmative to antihypertensive medications, the SBP level should be lowered to 140 mm Hg. Conclusion: This success rate-oriented simulation proposes that the SBP level to switch from lifestyle modifications to antihypertensive medications can be modulated according to the behavioral propensity for taking antihypertensive medications. Abbreviations: The following abbreviations are used in this manuscript: CVD: cardiovascular disease; LM: lifestyle modifications; AM: antihypertensive medications; IR CVD : incidence rate of cardiovascular disease (events/year); SBP: systolic blood pressure; ∆IR CVD : the improvements in the incidence rate of cardiovascular disease by lifestyle modifications and/or by antihypertensive medications.

This study aimed to investigate the association of gastrointestinal (GI) adverse events of cinacalcet with gallstones in the hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). A total of 23 HD patients under the treatment with cinacalcet and 101 control patients were enrolled in this cross-sectional study. We investigated the prevalence of gallstones and the association of GI adverse events of cinacalcet with gallstones. The prevalence of gallstones was significantly higher in the HD patients with cinacalcet compared with the controls (47.8% vs. 15.8%). The longer time on HD, hypercalcemia, hyperphosphatemia and elevated parathyroid hormone level were observed in the HD patients with cinacalcet. Besides, GI adverse events of cinacalcet were observed more frequently in the HD patients with gallstones compared with those without gallstones (odds ratio 13.5, 95% CI: 1.80-101). Therefore, screening for gallstones before dosing cinacalcet may reduce the risk of GI adverse events in SHPT patients.

Aims: To assess the effects of sodium-glucose co-transporter type 2 inhibitors on central blood pressure, an important determinant of cardiovascular events., Methods: Canagliflozin, Empagliflozin or Luseogliflozin was given for 102 type 2 diabetic patients with hypertension and nephropathy. Central blood pressure was evaluated by radial tonometry. Clinical parameters were followed for 6 months., Results: Three differing sodium-glucose co-transporter type 2 inhibitors similarly reduced brachial and central blood pressures, casual blood sugar, haemoglobin A1c, estimated glomerular filtration rate and albuminuria without significant changes in pulse rate and lipid profiles. Central systolic blood pressure was associated with the decreases in albuminuria by sodium-glucose co-transporter type 2 inhibitors., Conclusion: Comparable influences of various sodium-glucose co-transporter type 2 inhibitors on central blood pressure suggest class effects.

In this review, we focused on the relationship between central blood pressure and chronic kidney diseases (CKD). Wave reflection is a major mechanism that determines central blood pressure in patients with CKD. Recent medical technology advances have enabled non-invasive central blood pressure measurements. Clinical trials have demonstrated that compared with brachial blood pressure, central blood pressure is a stronger risk factor for cardiovascular (CV) and renal diseases. CKD is characterized by a diminished renal autoregulatory ability, an augmented direct transmission of systemic blood pressure to glomeruli, and an increase in proteinuria. Any elevation in central blood pressure accelerates CKD progression. In the kidney, interstitial inflammation induces oxidative stress to handle proteinuria. Oxidative stress facilitates atherogenesis, increases arterial stiffness and central blood pressure, and worsens the CV prognosis in patients with CKD. A vicious cycle exists between CKD and central blood pressure. To stop this cycle, vasodilator antihypertensive drugs and statins can reduce central blood pressure and oxidative stress. Even in early-stage CKD, mineral and bone disorders (MBD) may develop. MBD promotes oxidative stress, arteriosclerosis, and elevated central blood pressure in patients with CKD. Early intervention or prevention seems necessary to maintain vascular health in patients with CKD.

Background: Kidney resistive index (RI) correlates with tubulointerstitial changes and predicts renal prognosis. Most patients with chronic kidney diseases (CKDs) manifest high blood pressure and atherosclerotic cardiovascular diseases. In addition, various atherosclerotic indexes relate to variations in blood pressure., Methods: Subjects were 70 CKD patients, who visited our office and agreed to measure home blood pressure and receive renal ultrasonography. Cross-sectional analyses were performed., Results: Patient age was averaged 61 ± 15 (SD) y/o and 60% were male. Mean serum creatinine and proteinuria were 1.2 ± 0.5 mg/dl and 0.2 ± 0.5 g/gCr, respectively. Office blood pressure and kidney RI were 128 ± 17/75 ± 11 mmHg and 0.66 ± 0.08, respectively. Multivariate regression analysis revealed that age and office blood pressure independently correlated to kidney RI (p < 0.05 for each). Home blood pressure was averaged 122 ± 7/70 ± 6 mmHg. Both standard deviation and the maximal-minimal difference in home systolic blood pressure related to kidney RI (p < 0.05)., Conclusions: The present results indicate that office blood pressure correlates to kidney RI, which predicts renal prognosis. In addition, our data implicate that kidney RI relates to variations in home systolic blood pressure, and suggest that kidney RI may be a good index for atherosclerosis in CKD patients.

Objective It is difficult to compare directly the practical effects of lifestyle modifications and antihypertensive medications on reducing cardiovascular disease (CVD). The purpose of this study was to compare the hypothetical potential of lifestyle modifications with that of antihypertensive medications in reducing CVD in an aging society using a success rate-oriented simulation. Methods We constructed a simulation model for virtual Japanese subpopulations according to sex and age at 10-year intervals from 40 years of age as an example of an aging society. The fractional incidence rate of CVD was calculated as the product of the incidence rate at each systolic blood pressure (SBP) level and the proportion of the SBP frequency distribution in the fractional subpopulations of each SBP. The total incidence rate was calculated by the definite integral of the fractional incidence rate at each SBP level in the sex- and age-specific subpopulations. Results If we consider the effects of lifestyle modifications on metabolic factors and transfer them onto SBP, the reductions in the total incidence rate of CVD were competitive between lifestyle modifications and antihypertensive medications in realistic scenarios. In middle-aged women, the preventive effects of both approaches were limited due to a low incidence rate. In middle-aged men and extremely elderly subjects whose adherence to antihypertensive medications is predicted to be low, lifestyle modifications could be an alternative choice. Conclusion The success rate-oriented simulation suggests that the effectiveness of lifestyle modifications or antihypertensive medications in preventing cardiovascular events largely depends on the baseline incidence rate and sex- and age-specific behavioral factors.

Background: This study was attempted to investigate whether lifestyle modifications supported by regional health nurses should improve cardio-metabolic factors--including adipocytokines, oxidative stress, and arterial stiffness--in subjects with metabolic syndrome., Methods: Thirty-six subjects with metabolic syndrome were enrolled, 28 of whom completed the 6-month lifestyle modifications (male:female=19:9). Blood and urine test results were examined in relation to metabolic factors before and after 6-month nutritional and physical activity modifications. In addition, oral glucose tolerance tests were performed and arterial stiffness was measured by brachial-ankle pulse wave velocity and radial augmentation index before and after them., Results: Six-month lifestyle modifications significantly reduced body weight, homeostasis model assessment index, and low-density lipoprotein cholesterol (LDL-C). They significantly attenuated oxidative stress measured by the urinary 8-hydroxy-2-deoxyguanosine/creatinine ratio. They also lowered brachial and central systolic blood pressure. They tended to decrease waist circumferences and the levels of C-reactive protein. However they did not significantly change the levels of adipocytokines, including tumour necrosis factor, soluble tumour necrosis factor receptors, and interleukin 6, or arterial stiffness measured by brachial-ankle pulse wave velocity and radial augmentation index., Conclusions: Six-month lifestyle modifications supported by regional health nurses lowered body weight, insulin resistance, LDL-C, oxidative stress, and peripheral and central blood pressure in subjects with metabolic syndrome., (Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Health-related quality of life (HRQOL) is an important measure of how disease affects patients' daily life. Conventional in-center hemodialysis (CHD) patients have been found to have decreased HRQOL. Recent study reported that at-home hemodialysis (HHD) improved the long-term HRQOL compared with CHD; however, there have been no data from Japanese HHD patients. A sample of 80 Japanese hemodialysis patients (46 HHD and 34 CHD) was matched for age, sex, and cause of end-stage renal disease. Patient HRQOL was measured using two health surveys: Medical Outcomes Study 36 Item Short Form Health Survey-Version 2 and Kidney Disease Quality of Life-Short Form. HHD patients reported better scores on seven out of eight domains (all domains except general heath) of the Medical Outcomes Study 36 Item Short Form Health Survey-Version 2, as well as better Kidney Disease Quality of Life-Short Form scores with respect to symptoms and problems, effect of kidney disease, and work status. No significant differences were observed for burden of kidney disease, cognitive function, quality of social interaction, sexual function, or sleep. More than 65% of HHD patients stated that they were not bothered at all by limitations on food and water intake. Japanese HHD patients demonstrate significantly higher HRQOL scores. However, while their HRQOL and employment rate were high and they were able to enjoy fewer dietary restrictions, kidney disease remained a great burden., (© 2014 International Society for Hemodialysis.)

Background: The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension., Methods: Normotensive men (NT, n=60) and treated stage 2 and 3 essential hypertensive men (HT, n=89) were enrolled in this study. The relationship between TNF-related parameters and cardiorenal metabolic factors was examined in NT and HT, separately., Results: HT showed higher rates of insulin resistance and enhanced chronic inflammation compared with NT. The levels of soluble TNF receptor 1 and 2 were significantly higher in HT than in NT, although TNF-α levels were unexpectedly lower in HT than in NT. Regression analysis indicated that the TNF-related parameters were closely linked with mild renal dysfunction both in NT and HT, and moderately related to chronic inflammation only in HT. HT taking inhibitors of the renin-angiotensin system showed improved insulin resistance, but no difference in the TNF-related parameters., Conclusion: These results suggest that the disturbed TNF system is closely linked with chronic inflammation rather than with insulin resistance in HT.

Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension. Furthermore, daily variations of blood pressure are relatively large in patients treated with hemodialysis, partly due to ultrafiltration. Twenty hypertensive patients with end-stage renal diseases whose blood pressure was controlled by a single antihypertensive agent, either angiotensin receptor antagonist (ARB) or calcium channel blocker (CCB), were enrolled into the study. Home blood pressure measurements were also performed. Average systolic and diastolic blood pressures were similar between two agents. However, variations of systolic blood pressure during ARB treatment were greater than those of CCB, and maximal differences in daily systolic blood pressure during treatment with ARB (19±7 mmHg) were greater than those with CCB (14±6 mmHg, p<0.01). Systolic blood pressure measured after hemodialysis under ARB therapy (110±6 mmHg) was lower than that of CCB (118±6 mmHg, p<0.05). Daily variations of diastolic blood pressure were similar between ARB and CCB periods. Our results indicate that variations of systolic blood pressure during ARB treatment are larger than CCB, and suggest that CCB is useful to obtain the better quality of blood pressure control, improving blood pressure stability by preventing substantial drops in blood pressure in hypertensive patients with end-stage renal diseases.

Background/aims: Vitamin D increases renal expression of klotho in normotensive rats. Klotho reduces oxidative stress., Methods: In this study, we aimed to determine if vitamin D would suppress oxidative stress using 4 groups of hypertensive rats: uninephrectomized, stroke-prone, spontaneously hypertensive rats fed a high-salt (6%) diet (controls; C); those treated with irbesartan (I); those treated with calcitriol (V); and those treated with both irbesartan and calcitriol (I+V)., Results: Systolic blood pressure was higher in the C group than in the I and I+V groups. Albuminuria was attenuated in groups I, V, and I+V. Renal angiotensin II (AngII) concentration was lower in groups I and I+V than in group C, and plasma AngII levels of groups I and V were higher and lower than those in group C, respectively. Compared with group C, renal klotho expression, 8-epi-prostaglandin F2α excretion, and acetylcholine-induced decrease in blood pressure improved in the V and I+V groups., Conclusions: The data indicate that irbesartan effectively decreases blood pressure and renal AngII levels, and improves albuminuria. Our findings indicate that vitamin D enhances klotho expression, suppressing oxidative stress and albuminuria without substantial changes in renal AngII levels. These results suggest that the amelioration of endothelium function by vitamin D involves free klotho., (© 2014 S. Karger AG, Basel.)

A recent study indicated that, compared with glycated hemoglobin (HbA1c), glycated albumin (GA) provides a more accurate assessment of glycemic control in diabetic patients on hemodialysis. However, the suitability of GA for this purpose in peritoneal dialysis (PD) patients is questionable. We measured blood glucose, GA, HbA1c, serum albumin, protein losses in urine and dialysate, protein catabolic rate, hemoglobin, and dose of erythropoiesis-stimulating agents in 71 PD patients [20 with diabetes (DM), 51 without DM]. In both DM and non-DM patients, blood glucose levels correlated significantly with HbA1c (r = 0.47, p < 0.001), but not with GA (r = 0.18, p = 0.19). In patients with high serum albumin (> 3.2 g/dL), blood glucose levels correlated significantly with GA (r = 0.32, p = 0.047). Further, low protein losses in urine and dialysate (< 5.9 g daily) also significantly correlated with GA (r = 0.37, p = 0.041). In PD patients, HbA1c is better than GA as an indicator of blood glucose levels. Glycated albumin can be used as an indicator of glycemic control in PD patients with normal serum albumin and low protein losses in urine and dialysate.

Calcium channel blockers are the strongest and most widely used antihypertensive drugs in Japan. Calcium channel blockers dilate both artery and arteriole that increases end-organ perfusion, thus possessing few side effects especially for the elderly hypertensive patients. The safety of calcium channel blockers was well established. In this paper, important clinical evidence supporting the effectiveness of calcium channel blockers and improving cardiovascular endpoints will be reviewed. Calcium channel blockers protect end-organs from hypertensive vascular injury. In addition, calcium channel blockers show non-inferiority to angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics regarding cardiovascular endpoints. Furthermore, calcium channel blockers may have superiority to betablockers. Although cardiovascular protection by calcium channel blockers largely depends on their potent blood pressure lowering ability, including central blood pressure, calcium channel blockers can manifest blood pressure-independent vascular protection. Thus, calcium channel blockers are basic antihypertensive drugs, and constitute the treatment of choice to obtain target blood pressure for most hypertensive patients, especially for high-risk population and those with resistant hypertension. An intense treatment of hypertension with adequate doses of calcium channel blockers is mandatory to improve cardiovascular prognosis.

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, where excessive Th1 cell responses are observed. We performed experiments to identify immunologically bioactive proteins in human plasma and found that paraoxonase (PON)-1, which has esterase activity and is associated with high-density lipoproteins, inhibited the IFN-γ production by both murine and human differentiating Th1 cells. Trinitrobenzene sulfonic acid-induced colitis was attenuated by the administration of PON-1. The beneficial effects of PON-1 were associated with a reduced ratio of IFN-γ-producing CD4 T cells in the mesenteric lymph nodes and decreased production of T cell-related cytokines in the colon. PON-1 inhibited the TCR-induced activation of ERK-MAPK signaling and the nuclear translocation of NF-κB in CD4 T cells. Interestingly, an excessive CD4 T cell response was observed in PON-1-deficient mice under physiological and pathological conditions. Additionally, the efficacy of PON-1 or G3C9-C284A (G3C9), which shows a higher esterase activity than PON-1, on colitis was similar to that of an anti-TNF-α mAb, which is a clinically used CD treatment. Moreover, G3C9 more effectively suppressed CD4(+)CD45RB(high) cell transfer-induced chronic colitis in mice than did PON-1, and the efficacy of G3C9 against the colitis was similar to that of the anti-TNF-α mAb. Therefore, PON-1 (or G3C9) administration may be clinically beneficial for CD patients.

Previous studies have reported that high-salt intake paradoxically activates tubuloglomerular feedback (TGF) in type 1 diabetes. Using Zucker lean (ZL) and diabetic fatty (ZDF) rats on normal and high-salt diets, renal hemodynamics and the renin-angiotensin system (RAS) were characterized. On normal salt diet, glomerular filtration rate (GFR) was higher in ZDF than ZL rats. Autoregulation of GFR was less efficient and lithium clearance was lower in ZDF rats than ZL rats. Salt load reduced GFR in ZDF rats with restoration of lithium clearance and partial improvement in autoregulatory index (AI). The administration of 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine-1 receptor antagonist to ZDF rats on a high-salt diet abolished the improvement of AI in GFR. However, this effect was seen by neither (Cx40)GAP27 nor (Cx37,43)GAP27, which inhibits connexin (Cx) 40 or Cx37. Renal ANG II was higher in ZDF than ZL rats on normal salt diet, but the difference was eliminated by a salt load. The present data provide the first demonstration for a salt paradox in type 2 diabetes and implicate that in addition to Cx alterations, an enhanced proximal reabsorption attenuates TGF, underlying glomerular hyperfiltration and RAS activation. These data suggest that a high-salt diet standardizes distal delivery in diabetes, suppressing the RAS, and improving GFR autoregulation and hyperfiltration through adenosine.

Zinc deficiency leads to decreased cellular immune responses. The overproduction of nitrogen species derived from inducible nitric oxide synthase (iNOS), its enzyme, and interleukine-1 beta (IL-1β), and inflammatory cytokine have been implicated in immune responses. The goal of this study was to investigate the effects of lipopolysaccharide (LPS)-induced changes in NO metabolites, iNOS, and IL-1β protein expression in the lungs of zinc-deficient rats. Male Sprague-Dawley rats (body weight, 100 g) were divided into two groups and were fed either a zinc-deficient diet (ZnD) or a zinc-containing diet (Cont). After 4 weeks on these diets, rats received a 10-mg/kg dose of LPS injected via the tail vein and were then maintained for an additional 72 h. To determine total NO concentrations in the blood, serum zinc concentration, iNOS protein expression, IL-1β, and iNOS immunohistochemistry, blood and lung samples were obtained at pre-LPS injection, 5, 24, and 72 h after injection. Total NO levels were significantly increased at 5, at 24, and at 72 h after LPS injection compared with pre-LPS injection level in ZnD group; significant changes in total NO levels was elevated at 5 h from at pre-LPS level but not significant changes from basal level at 24 and 72 h in the control group. Based on western blot analyses and immunohistochemistry, clear bands indicating iNOS and IL-1β protein expression and iNOS antibody-stained inflammatory cells were detected at 5 and 24 h in the ZnD group and 5 h in the Cont group, not observed at 24 and 72 h in the control group. These results suggest that zinc deficiency induces overexpression of iNOS and IL-1β proteins from inflammatory cells around the alveolar blood vessels, resulting in overproduction of total NO and persisted inflammatory response in the zinc-deficient rat lung. Taken together, overexpression of LPS-induced iNOS, overproduction of iNOS-derived NO, and overexpression of IL-1β may induce nitrosative and oxidative stresses in the lung, and these stresses may be involved low immunity of zinc deficiency states.

Background: Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD)., Methods: The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure., Results: Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 ± 1 vs. -2 ± 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group (-29 ± 2 vs. -38 ± 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (-4 ± 1 vs. -9 ± 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period., Conclusion: In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection., (Copyright © 2012 S. Karger AG, Basel.)

Background: In practice, it is difficult to compare the effectiveness of traditional antihypertensive treatment with that of health promotion in reducing incidence rate of cardiovascular disease (IRCVD, events/year). This simulation study compared the effectiveness of two approaches to reducing IRCVD in a sample population: a traditional approach, in which high-risk patients are treated with conventional antihypertensive medications, and a population-based approach, in which subjects participate in a health promotion program., Methods: We constructed a simulation model for a sample population of middle-aged Japanese men whose systolic blood pressure (SBP) levels are normally distributed (130 ± 20 mm Hg). The principal assumption was that IRCVD increases exponentially according to SBP. The population IRCVD was calculated as the product of the distribution of SBP multiplied by IRCVD at each SBP. The cumulative IRCVD was calculated by the definite integral from the lowest to the highest SBP of IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively., Results: The reduction in IRCVD was twice as large for antihypertensive medications as it was for health promotion in several situations. For example, if adherence to antihypertensive treatment occurred at a realistic level, the decrease in IRCVD was estimated at 9.99 × 10(-4). In contrast, even if the health program was promoted optimistically, the decrease in IRCVD was estimated at 4.69 × 10(-4)., Conclusions: The success rate-oriented simulation suggests that prescribing antihypertensive medications is superior to promoting the health promotion program in reducing IRCVD in virtual middle-aged Japanese men.

Renoprotective effects of renin-angiotensin system inhibitors are well known. However, hypertension with chronic kidney diseases (CKDs) is usually hard to manage with a single agent, and requires the addition of either a calcium antagonist or diuretics to achieve the goal of blood pressure (BP) lowering. Retrospective study was performed among the patients who regularly visited our office, and whose BP had not reached the goal of BP despite of treatment with an angiotensin receptor blocker. Clinical parameters were observed for 6 months. Comparisons of home BP and proteinuria were made between 16 patients prescribed additional calcium antagonists and 15 patients with diuretics. Patient background including age, sex BP, augmentation index, and renal function were similar between the two groups. Both calcium antagonists and diuretics considerably decreased BP. An addition of either agent resulted in similar control of home BP. While both agents reduced augmentation index (AI), calcium antagonist exerted greater improvements in AI (-7 ± 5 vs. -4 ± 3%, p < 0.01). Although urinary protein excretion in both groups was decreased, the degree of these decreases was greater among the patients treated with a calcium antagonist (-28 ± 15 vs. -11 ± 15%, p < 0.01). During observation periods, eGFR in both groups did not show any significant changes from the base line. Under the inhibition of a renin-angiotensin system, calcium antagonists elicited a greater decrease in urinary protein excretion than diuretics when BP similarly controlled. Calcium antagonists also improved AI more strongly than diuretics. Calcium antagonists appear suited for adding on renin angiotensin system inhibitors to treat hypertension with CKDs.

Telmisartan is an angiotensin type 1 receptor blocker (ARB), which also partially activates liganding peroxisome proliferator-activated receptor gamma. However, the relationship between the effects of telmisartan on hemodynamics and metabolism has not sufficiently been elucidated in clinical settings. We examined the long-term effects of telmisartan on hemodynamics including home blood pressure (BP) and on insulin resistance representing as homeostasis model assessment (HOMA-R). Twenty-seven hypertensive patients were consecutively enrolled at our outpatient department. At entry, all of the participants were previously prescribed another ARB for more than 3 months and then the former ARB were replaced by telmisartan. Hemodynamic and metabolic parameters were measured before treatment and at points 1 and 3 months after treatment with telmisartan. Telmisartan significantly lowered home systolic blood pressure (SBP) and diastolic blood pressure (DBP) (DBP) and improved HOMA-R during the treatment period. However, the changes in home SBP and DBP were not correlated with that of HOMA-R. In conclusion, telmisartan lowers home BP and improves insulin resistance without correlation between their changes.

Aim. Height is an important determinant of augmentation index (AI) that anticipates cardiovascular prognosis. There is a scanty of the data whether short height predicts survival in patients with end-stage renal diseases, a high risk population. Methods. Fifty two hypertensive patients with type 2 diabetic nephropathy receiving hemodialysis and 52 patients with nondiabetic nephropathy were enrolled. In addition to AI estimated with radial artery tonometry, classical cardiovascular risk factors were considered. Patients were followed for 2 years to assess cardiovascular prognosis. Results. Cox hazards regression revealed that both smoking and shortness in height independently contributed to total mortality and indicated that smoking as well as the presence of left ventricular hypertrophy predicted cardiovascular mortality. Our findings implicated that high AI, the presence of diabetes, and low high-density lipoprotein cholesterol were significant contributors to cardiovascular events. Conclusions. Our findings provide new evidence that shortness in height independently contributes to total mortality in hemodialysis patients.

Although the patients with diabetic nephropathy suffered high cardiovascular risk, augmentation index (AI) in diabetic nephropathy has been poorly characterized. Cross-sectional studies were performed on 26 diabetic and 27 nondiabetic nephropathic patients. Home blood pressure was examined. In addition, blood pressure, pulse rate, and AI were measured in both supine and sitting positions. Patient backgrounds such as age, sex, sitting blood pressure, and pulse rate were similar between two groups. Circadian variations of home blood pressure were preserved in nondiabetic patients, but disappeared in diabetes. Changing from supine to sitting position induced greater decrements of systolic blood pressure (DeltaSBP -9 +/- 8 mmHg) and AI (DeltaAI -7 +/- 10) in the diabetic group than in nondiabetic patients (DeltaSBP -4 +/- 12 mmHg, DeltaAI -2 +/- 9). Multivariate regression analysis revealed that AI in a sitting position correlated positively to SBP and inversely to pulse rate. Of interest, AI in supine position related positively to age, the presence of diabetes and SBP, and inversely to pulse rate. The present data indicate autonomic dysfunction in patients with diabetic nephropathy. Furthermore, our findings provide the evidence that autonomic dysfunction elicits an inadequate physiological arterial contraction in response to postural change, thereby reducing AI that results in the fall of SBP. Finally, the present results suggest that AI in supine, but not sitting position, is suited for detecting cardiovascular risk in diabetes.

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) levels >or=180 and/or 110 mm Hg and <120/80 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.

Macrophages uptake oxidized low-density lipoprotein (LDL) via a scavenger receptor such as CD36 from plasma, and then become foam cells. We examined the association of CD36 gene single nucleotide polymorphisms (SNPs) with certain metabolic characteristics in a young male Japanese population (n = 494). The G allele in a SNP located at +30215 on the 3'-untranslated region (UTR) was significantly correlated with the plasma LDL-cholesterol concentrations (r = 0.13, p <0.01). The difference in LDL-cholesterol concentrations was 10 mg dl(-1) between GG- and AA-genotype carriers (p <0.05). The CD36 gene SNP is a novel maker of the variation in the LDL-cholesterol levels in young Japanese men.

Our previous data indicated that both home blood pressure and arterial stiffness predicted the progression of renal dysfunction in the patients with chronic kidney diseases. In the present study, we examined both home blood pressure and the parameters of arterial stiffness as the indicator to the progression of chronic kidney diseases. Forty-two nondiabetic chronic kidney disease patients were enrolled and followed for 1 year. Anti-hypertensive therapy was adjusted to achieve office blood pressure below 130/80 mmHg. Home blood pressure was examined twice a day in the morning and evening. Pulse wave velocity (PWV) and augmentation index (AI) were measured as the index of arterial stiffness. The time for reflection (TR) was also determined. The relationship of annual changes in serum creatinine (Scr) with the above parameters was assessed. Multivariate regression analysis revealed that TR inversely correlated to annual increase in Scr (beta = -0.03, p < 0.05). Home blood pressure did not correlate to annual changes in Scr in the present study. The present data indicated that arterial stiffness is elevated despite good blood pressure control in chronic kidney disease, especially among the dippings. In addition, our data suggest that PWV and AI correlated to each other, while they were influenced differently by hemodynamic factors. Finally, the present findings provide the evidence that the arterial stiffness parameter is more sensitive than home blood pressure as an indicator to the progression of chronic kidney disease.

Introduction: Recombinant human soluble thrombomodulin (rhsTM) is newly developed for the treatment of DIC. The purpose of this study was to evaluate the efficacy of the concomitant administration of rhsTM and antithrombin (AT)., Methods: In the first series, rats were treated with either 62.5, 125, 250 or 500 IU/kg (n = 6, each) of AT or 0.125, 0.25, 0.5 or 1.0 mg/kg (n = 6, each) of rhsTM followed by lipopolysaccharide (LPS) injection. 8 h later, the fibrinogen level was examined. In the second series, TM group was pretreated with 0.25 mg/kg of rhsTM, AT group was pretreated with 125 IU/kg of AT, AT/TM group was pretreated with both AT and rhsTM, and control group was pretreated with saline (n = 7, each). The platelet count, fibrinogen, ALT, LDH and high-mobility group box 1 (HMGB1) levels were measured. In addition, histologic changes in liver were examined. In the third series, survival was calculated up to 24 h., Results: Both AT and rhsTM produced a linear dose-response with regard to the fibrinogen level, with 125 IU/kg of AT and 0.25 mg/kg of rhsTM producing equivalent effects. The combined administration of AT and rhsTM significantly reduced the decrease in the platelet count and the fibrinogen level (P < 0.05, 0.01, respectively). The elevations in ALT and LDH were significantly suppressed in all treatment groups. The HMGB1 level and the histologic changes tended to indicate damage reduction. Survival was significantly better only in AT/TM group (P < 0.01)., Conclusions: The coadministration of AT and rhsTM might be effective for the treatment of severe sepsis.

We investigated the effects of antithrombin, a plasma inhibitor of coagulation factors, in rats with puromycin aminonucleoside-induced nephrosis, which is an experimental model of human nephrotic syndrome. Antithrombin (50 or 500 IU/kg/i.v.) was administered to rats once a day for 10 days immediately after the injection of puromycin aminonucleoside (50 mg/kg/i.v.). Treatment with antithrombin attenuated the puromycin aminonucleoside-induced hematological abnormalities. Puromycin aminonucleoside-induced renal dysfunction and hyperlipidemia were also suppressed. Histopathological examination revealed severe renal damage such as proteinaceous casts in tubuli and tubular expansion in the kidney of control rats, while an improvement of the damage was seen in antithrombin-treated rats. In addition, antithrombin treatment markedly suppressed puromycin aminonucleoside-induced apoptosis of renal tubular epithelial cells. Furthermore, puromycin aminonucleoside-induced increases in renal cytokine content were also decreased. These findings suggest that thrombin plays an important role in the pathogenesis of puromycin aminonucleoside-induced nephrotic syndrome. Treatment with antithrombin may be clinically effective in patients with nephrotic syndrome.

Little research has been conducted into the long-term effects of preeclampsia, despite its frequent occurrence. The aim of this review is to examine the association between preeclampsia and the development of hypertension and kidney diseases later in life. To achieve this aim, we evaluated three retrospective studies conducted in our department. In the first study, 52 women who suffered from preeclampsia during their first pregnancy were followed for 2 years after delivery for any long-term effects upon blood pressure. In the second study, we evaluated HOMA-R, pulse wave velocity and augmentation index in groups of 48 postmenopausal women with a past history of preeclampsia and 204 postmenopausal women without a past history of preeclampsia. In the third study, we examined the association between a past history of preeclampsia and chronic kidney disease based on biopsy in 127 postmenopausal women. From the first study, although there were no significant differences in age, blood pressure at the onset of preeclampsia, the levels of proteinuria and the birth weight of the child between women who remained hypertensive and those who became normotensive, body mass index was significantly larger in women who remained hypertensive compared to those who were normotensive. In the second study, we found that women with a past history of preeclampsia exhibited insulin resistance combined with reduced vascular elasticity. In the third study, of 32 patients with a past history of preeclampsia, 12 patients exhibited focal segmental glomerulosclerosis, 10 exhibited IgA nephropathy and 10 exhibited nephrosclerosis. In contrast, of the women without a past history of preeclampsia, 26 patients exhibited IgA nephropathy, 20 exhibited a minimal change in nephritic syndrome, 6 exhibited nephrosclerosis, 6 exhibited membranous nephropathy, 5 exhibited lupus nephritis, 5 exhibited diabetic nephropathy, and 27 exhibited various nephropathies. None of the women without a past history of preeclampsia exhibited focal segmental glomerulosclerosis. Taken together with previous results, these findings suggest that hypertension and chronic kidney disease in postmenopausal women are closely associated with a past history of preeclampsia.

Aim: Cardiovascular disease constitutes a major cause of death in patients with chronic kidney diseases and is related to enhanced arterial stiffness. It has been reported that daytime hemodialysis patients show better prognosis than evening hemodialysis patients., Methods: Aortic augmentation index (AI) and radial AI were measured in 20 non-diabetic hemodialysis patients, using SphygmoCor (PWV Medical) and HEM-9010AI (Omron Healthcare) as markers of arterial stiffness. Cardiovascular prognosis was followed for two years., Results: Mean age, blood pressure, pulse rate, and aortic and radial AI were 52 +/- 4 y/o, 142 +/- 6/74 +/- 4 mmHg, 78 +/- 4 bpm, 21 +/- 2, and 71 +/- 4%, respectively, in 10 daytime hemodialysis patients, and they averaged 52 +/- 3 y/o, 146 +/- 6/76 +/- 4 mmHg, 74 +/- 3 bpm, 26 +/- 2, and 73 +/- 3% in 10 evening hemodialysis patients, respectively. Thus, aortic AI was higher in evening hemodialysis patients (p < 0.05). In all, one patient was hospitalized due to cardiovascular complications in daytime hemodialysis patients, as well as three patients from those dialyzed in the evening., Conclusion: Although a larger scale study is required to draw a definite conclusion, our findings suggest that a better prognosis in daytime hemodialysis non-diabetic patients is related to the lower AI.

Background: Intracellular Ca(2+) ([Ca(2+)](i)) may be a factor of importance to hypertension in spontaneously hypertensive rats (SHR). Platelet hyperactivity caused by increased [Ca(2+)](i) may contribute to atherothrombotic cardiovascular events. In a genome scan, we have recently demonstrated that a candidate quantitative trait locus (QTL) for [Ca(2+)](i) in platelets is located near the sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (Serca) II gene locus on chromosome 12 in backcrossed rats derived from SHR and normotensive Fischer 344 rats (F344)., Methods: Congenic substitution mapping was performed for the chromosomal region including the Serca II gene locus. The segment including the Serca II gene locus was transferred from F344 onto the genetic background of the progenitor SHR. Systolic blood pressure (SBP), platelet aggregation, and ratio of heart weight to body weight (HW/BW) as well as [Ca(2+)](i) responses in platelets were compared between SHR and the congenic strain., Results: Among the parental strains, thrombin-stimulated and thapsigargin-induced peak values of [Ca(2+)](i) in platelets, platelet aggregation, SBP, and HW/BW were significantly greater in SHR than in F344 and F(1) rats. The heterozygous congenic rats for the Serca II gene segment had significantly attenuated [Ca(2+)](i) responses and platelet aggregation compared with SHR. Furthermore, they demonstrated significantly lower SBP and HW/BW., Conclusion: Congenic substitution mapping clarified that a chromosomal segment including the Serca II gene locus was responsible for attenuated [Ca(2+)](i) responses and platelet aggregation in the heterozygous congenic rats. Therefore, this chromosomal region may contribute to the development of hypertension and cardiac hypertrophy by augmenting Ca(2+) signaling in SHR.

Insulin resistance prevails not only among diabetic patients but also among hypertensive and obese patients. The relationship between insulin resistance and cardiovascular diseases was investigated in hemodialysis (HD) patients. Eighty-one maintenance HD patients were enrolled. The homeostasis model assessment of insulin resistance (HOMA-IR) method was used to assess insulin resistance. The relationship of HOMA-IR with cardiovascular and all-cause events was assessed. Compared with nondiabetic patients (n = 55), diabetic patients (n = 26) showed higher HOMA-IR (2.5 +/- 0.3 vs 1.4 +/- 0.2, P < .05), lower ankle-brachial pressure index (ABI, 0.85 +/- 0.09 vs 1.12 +/- 0.02, P < .01), and shorter HD duration (3 +/- 1 vs 9 +/- 1 years, P < .01), although their body mass index was similar (22.3 +/- 0.5 vs 21.5 +/- 0.4 kg/m(2)). Nondiabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 36) had lower HOMA-IR (1.2 +/- 0.2 vs 1.8 +/- 0.4, P < .05) and higher ABI (1.18 +/- 0.02 vs 1.02 +/- 0.05, P < .01) than those without (n = 17). Cardiovascular events were less common in HD patients with normal HOMA-IR (P < .05) or ABI (P < .01). Our data indicate that 69% of diabetic and 27% of nondiabetic patients have HOMA-IR greater than 1.6, implying reduced insulin sensitivity in HD patients. The present results provide evidence that angiotensin inhibition improves insulin resistance, possibly preventing vascular injury in HD patients. Finally, our findings suggest that insulin resistance is prognostic of cardiovascular events in HD patients.

The purpose of this study is to retrospectively analyze the clinical characteristics of patients with diabetes mellitus who started dialysis therapy. First, we reviewed 120 cases of end-stage renal failure due to diabetic nephropathy who started dialysis therapy in 1996 and 1997. Presenting features were as follows: men, 62.5%; mean age at starting dialysis, 57 +/- 1 year; and mean serum creatinine level, 7.3 +/- 0.2 mg/dl. To find any clinical characteristics in the population, we divided patients into three groups according to age, as follows: Young age group (<40 years old: 12 patients), Senior age group (>65 years: 32 patients) and Middle age group: 76 patients (>40 and <65 years). The Young age group, (mean age: 36 +/- 1 years) had lower serum creatinine levels (6.1 +/- 0.4 mg/dl) (p < 0.05) and greater cardio-thoracic ratio (61.1 +/- 1.3%) (p < 0.05), obtained from the chest X-ray film, than the other two groups. There were no significant differences between the Middle age group (59 +/- 1 year) and the Senior age group (72 +/- 1 year) in the levels of serum creatinine and cardio-thoracic ratio. To further analyze the clinical characteristics, the other 113 patients in 1998 and 1999 who were matched with the Middle age group in the former study, were retrospectively analyzed. The mean age was 61 +/- 2 years, and the proportion of men was 54% (62/113). The percentage of changes in body weights were as follows: 9.5 +/- 2.8% (p < 0.05) from teens to 20s and 19.2 +/- 3.2% (p < 0.05) from teens to 30s in men. The percentage of changes in body weight in women were as follows: 9.6 +/- 2.1% (p < 0.05) from teens to 30s and 18.6 +/- 2.4% (p < 0.05) from teens to 40s. The age at the start of dialysis therapy was 54 +/- 2 years old in men and 59 +/- 3 years in women. There was a significant difference (p < 0.05) between men and women. In summary, the study suggests that young patients with diabetic nephropathy received dialysis therapy because of hypervolemic symptoms compared to older patients, and that renal deterioration progressed more rapidly in male subjects than in female subjects with diabetic nephropathy. These differences should be borne in mind in clinical practice.

Salt is essential and important for maintaining life. Excess salt intake produces an increase in blood pressure. In several subpopulations of patients with hypertension, such as those with obesity, post-menopausal women, and patients with chronic kidney diseases, for example, salt sensitivity is based on a pressure-natriuresis mechanism. In this mechanism, neuro-humoral regulation is mainly responsible for sodium handling. In addition, NO has a powerful effect on the pressure-natriuresis mechanism. Based on this mechanism, progression of chronic kidney disease is governed by salt uptake. Moreover, a genetic component for salt sensitivity is important in normotensive subjects with a family history of hypertension. In these regards, modulation of salt is of utmost importance in the fields of hypertension and nephrology.

Background: Increased intracellular calcium ([Ca2+]i) in platelets is also proposed as an intermediate phenotype for hypertension in spontaneously hypertensive rats (SHR). Increased [Ca2+]i in platelets is hypothesized to contribute to atherothrombotic events. Platelet hyperactivity is frequently associated with cardiovascular disease., Methods: In a genome scan, we performed the quantitative trait loci (QTL) mapping for [Ca2+]i in back-crossed rats derived from SHR and normotensive Fischer 344 rats, which demonstrated a single major QTL for hypertension on chromosome 1. Thrombin-stimulated [Ca2+]i in Ca2+-free and in Ca2+-containing buffers was measured in platelets using the Fura-2 method., Results: Among the parental strains, systolic blood pressure and thrombin-stimulated [Ca2+]i were significantly greater in SHR than in Fischer 344 and F1 rats. The sarco(endo)plasmic reticulum Ca2+-dependent ATPase II gene locus (Serca2) between D12Mgh5 and D12Mgh6 showed the significant linkage for thrombin-stimulated [Ca2+]i in Ca2+-free and Ca2+-containing buffers. The peak logarithm of the odds scores were 3.6 and 3.3, respectively. These QTL explained 19.8% and 17.4% of the total variances, respectively. D3Mit13 and DXMgh1 showed suggestive linkage for thrombin-stimulated [Ca2+]i in Ca2+-free and in Ca2+-containing buffers, respectively. The peak logarithm of the odds scores were 2.6 and 2.1, respectively., Conclusions: A significant QTL for [Ca2+]i was mapped near Serca2 on chromosome 12, and suggestive QTL were identified near D3Mit13 and DXMgh1 in a genome scan. Genetic abnormalites in platelet [Ca2+]i may contribute to cardiovascular disease via platelet hyperactivity, independent of blood pressure elevation.

The metabolic syndrome is characterized by a blunted insulin-mediated glucose uptake in various cell types. We compared the glucose uptake characteristics of Epstein-Barr virus (EBV)-transformed lymphoblasts obtained from young men with vs without metabolic and cardiovascular evidence of metabolic syndrome. From a population of 218 men, 20- to 25-year-old, 10 men with a systolic blood pressure (BP) > or =130 mm Hg and family history of hypertension were assigned to a high BP (HBP) group, and 10 with a BP < or =110 mm Hg, and no family history of hypertension was assigned to a low BP (LBP) group. Multiple clinical and metabolic characteristics were examined in both groups and compared. Peripheral lymphocytes from HBP and LBP subjects were EBV-transformed, and the glucose transporter (Glut)-mediated glucose uptake from each group was compared in lymphoblasts. Body mass index, fasting glucose, immunoreactive insulin, insulin resistance index based on a homeostasis model assessment (HOMA-R), and total and low-density lipoprotein cholesterol were significantly higher in the HBP than the LBP subgroup (whole-body insulin resistance). Baseline Glut-mediated and Glut-mediated insulin-stimulated glucose uptake by lymphoblasts from the HBP group were significantly lower than by lymphoblasts from the LBP group (cellular insulin resistance). The net increment in Glut-mediated glucose uptake by insulin was inversely correlated with HOMA-R. In conclusion, cellular insulin resistance in EBV-transformed lymphoblasts is associated with young Japanese subjects with HBP. The net increment in Glut-mediated glucose uptake by insulin in lymphoblasts may be a useful intermediate phenotype to study genetic aspects of the metabolic syndrome.

To search a gene(s) conferring susceptibility to type 2 diabetes mellitus, we genotyped nearly 60,000 gene-based SNPs for Japanese patients and found evidence that the gene at chromosome 6p12 encoding transcription-factor-activating protein 2beta (TFAP2B) was a likely candidate in view of significant association of polymorphism in this gene with type 2 diabetes. Extensive analysis of this region identified that several variations within TFAP2B were significantly associated with type 2 diabetes [a variable number of tandem repeat locus: chi(2)=10.9, P=0.0009; odds ratio=1.57, 95% CI 1.20-2.06, intron 1+774 (G/T); chi(2)=11.6, P=0.0006; odds ratio=1.60, 95% CI 1.22-2.09, intron 1+2093 (A/C); chi(2)=12.2, P=0.0004; odds ratio=1.61, 95% CI 1.23-2.11]. The association of TFAP2B with type 2 diabetes was also observed in the UK population. These results suggest that TFAP2B might be a new candidate for conferring susceptibility to type 2 diabetes and contribute to the pathogenesis of type 2 diabetes.

Objectives: Insulin resistance is associated with chronic renal failure, which may amplify its cardiovascular pathologic manifestations. We previously showed the presence of insulin resistance in mild renal insufficiency due to chronic glomerulonephritis. These observations may be explained by a decrease in insulin sensitivity due to renal dysfunction. The aim of the present study was to evaluate the effects of unilateral and subtotal nephrectomy on insulin sensitivity., Methods: Unilateral heminephrectomy and five-sixths nephrectomy (5/6Nx) were performed in male Sprague-Dawley rats, measuring steady-state plasma glucose (SSPG) during the insulin suppression test., Results: The glomerular filtration rate (GFR) decreased significantly from sham-operated rats, to unilateral heminephrectomy group, to 5/6Nx rats. SSPG was unexpectedly lower in the unilateral heminephrectomy group than in controls, suggesting that unilateral heminephrectomy increased the sensitivity to insulin despite a mild decrease in renal function. However, when the analysis was limited to the 5/6Nx group, SSPG was inversely correlated with GFR (r = -0.65, p < 0.05). When renal failure caused by 5/6Nx had reached end stage, the rats became insulin resistant, despite a profound reduction in renal mass., Conclusion: It is suggested that unilateral heminephrectomy reduced GFR and increased the sensitivity to insulin. When rats became uremic, insulin sensitivity decreased, even, in 5/6Nx.

To investigate the role of ryanodine receptors in glomerular arterioles, experiments were performed using an isolated perfused hydronephrotic kidney model. In the first series of studies, BAYK-8644 (300 nM), a calcium agonist, constricted afferent (19.6 +/- 0.6 to 17.6 +/- 0.5 microm, n = 6, P < 0.01) but not efferent arterioles. Furthermore, BAYK-8644 elicited afferent arteriolar oscillatory movements. Subsequent administration of nifedipine (1 microM) inhibited both afferent arteriolar oscillation and constriction by BAYK-8644 (to 19.4 +/- 0.5 microm). In the second group, although BAYK-8644 constricted afferent arterioles treated with 1 microM of thapsigargin (19.7 +/- 0.6 to 16.8 +/- 0.6 microm, n = 5, P < 0.05), it failed to induce rhythmic contraction. Removal of extracellular calcium with EGTA (2 mM) reversed BAYK-8644-induced afferent arteriolar constriction (to 20.0 +/- 0.5 microm). In the third series of investigations, ryanodine (10 microM) but not 2-aminoethoxyphenyl borate (100 microM) abolished afferent arteriolar vasomotion by BAYK-8644. In the fourth series of experiments, in the presence of caffeine (1 mM), the stronger activation of voltage-dependent calcium channels by higher potassium media resulted in greater afferent arteriolar constriction and faster oscillation. Our results indicate that L-type calcium channels are rich in preglomerular but not postglomerular microvessels. Furthermore, the present findings suggest that either prolonged calcium influx through voltage-dependent calcium channels (BAYK-8644) or sensitized ryanodine receptors (caffeine) is required to trigger periodic calcium release through ryanodine receptors in afferent arterioles.