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Background: Data on the risk of cardiovascular-related mortality in patients with cancer are limited., Methods and Results: This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years., Conclusions: Cancer survivors have a higher risk of fatal heart disease than the general population.

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Shear wave (SW) imaging is a novel ultrasound-based technique for assessing tissue characteristics. SW elasticity may be useful to assess the severity of hypertensive left ventricular (LV) hypertrophy. This study aimed to evaluate the efficacy of SW elasticity for assessing the degree of myocardial hypertrophy using hypertensive rats. Rats were divided into hypertension group and control group. SW elasticity was measured on the excised heart. Myocardial hypertrophy was assessed histologically. LV weight was greater in hypertension group. An increase in interventricular septum and LV free wall thicknesses was observed in hypertension group. SW elasticity was significantly higher in hypertension group than in control group (14.6 ± 4.3 kPa vs. 6.5 ± 1.1 kPa, P < 0.01). The cross-sectional area of cardiomyocytes was larger in hypertension group than in control group (397 ± 50 μm 2 vs. 243 ± 14 μm 2 , P < 0.01), and SW elasticity was positively correlated with the cross-sectional area of cardiomyocytes (R = 0.96, P < 0.01). This study showed that SW elasticity was higher in hypertensive rats and was closely correlated with the degree of myocardial hypertrophy, suggesting the efficacy of SW elasticity for estimating the severity of hypertensive LV hypertrophy., (© 2021. The Author(s).)

Left ventricular hypertrophy (LVH) is often seen in patients with primary aldosteronism (PA), and the prevalence of LVH is reportedly higher among patients with PA than patients with essential hypertension. However, the correlation between aldosterone levels and LVH is undefined, and how aldosterone affects LVH in patients with PA remains unclear. We, therefore, retrospectively assessed a large PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) to reveal the factors associated with LVH in patients with PA without suspected autonomous cortisol secretion. In the 1186 patients with PA studied, the basal plasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio did not significantly correlate with left ventricular LV mass index (LVMI) in single or multiple regression analyses. However, the plasma aldosterone concentration after the captopril challenge test or saline-infusion test, which are associated with autonomous aldosterone secretion, correlated significantly with LVMI, even after adjusting for patients' backgrounds, including age and blood pressure. In addition, hypokalemia and the unilateral subtype also correlated with LVMI. Longitudinal subanalysis of medically or surgically treated patients with PA showed significant reductions in LVMI in both the surgery (63.0±18.1 to 55.3±19.5 g/m 2.7 , P <0.001) and drug treatment (56.8±14.1 to 52.1±13.5 g/m 2.7 , P <0.001) groups. Our results suggest the autonomous aldosterone secretion level, not the basal aldosterone level itself, is relevant to LVH in patients with PA. In addition, the elevated LVMI seen in patients with PA is at least partially reversible with surgical or medical treatment.

Hyperuricemia has been reported to be a risk factor for hypertension, but this association may be affected by alcohol consumption. This study aimed to investigate whether hyperuricemia remains a risk factor for hypertension after eliminating the effect of alcohol consumption. This study comprised 7848 participants (4247 men and 3601 women) aged 30-74 years without hypertension who had undergone a medical checkup between April 2008 and March 2009 at Saku Central Hospital, Nagano Prefecture, Japan. Hyperuricemia was defined as uric acid >7.0 mg/dl in men, ≥6.0 mg/dl in women, and/or receiving treatment for hyperuricemia or gout. The incidence of hypertension was defined as the first diagnoses of blood pressure ≥140/≥ 90 mmHg and/or initiations of antihypertensive drug treatment. Multivariable-adjusted hazard ratios (HRs) of hyperuricemia for the incidence of hypertension after adjustment for and classification by alcohol consumption were estimated using the Cox proportional hazard model. During a mean of 4.0 years of follow-up, 1679 individuals developed hypertension. After adjustment for alcohol consumption, the HRs (95% confidence interval) associated with hyperuricemia were 1.37 (1.19-1.58) in men and 1.54 (1.14-2.06) in women. Among nondrinkers, the HR was 1.29 (0.94-1.78) in men with hyperuricemia compared with men without, and the corresponding HR was 1.57 (1.11-2.22) in women. The corresponding HR was 1.88 (1.27-2.86) in all participants with baseline blood pressure <120/80 mmHg. The interactions between hyperuricemia and sex (P = 0.534) and between drinking and sex (P = 0.713) were not significant. In conclusion, hyperuricemia predicts the risk for developing hypertension independent of alcohol drinking status.

Background: Relationships between blood glucose (BG) levels and insulin action, and incidence of hypertension have not been well known epidemiologically. This study aimed to investigate the association between indices of diabetes and the incidence of hypertension and compare the predictive powers of these indices in middle-aged Japanese., Methods: This 5-year cohort study included 2,210 Japanese aged 30-64 years without hypertension. Hazard ratios of high fasting blood glucose (FBG) levels, high post-loaded BG levels, high glycated hemoglobin (HbA1c) levels, insulin resistance (defined by homeostasis model assessment of insulin resistance [HOMA-IR]) and impaired insulin secretion at baseline for the incidence of hypertension were estimated using multivariable-adjusted Cox proportional hazard models. Hypertension was defined as blood pressure ≥ 140/90 mm Hg or receiving antihypertensive treatment., Results: During the follow-up, 456 participants developed hypertension. After adjustment for HbA1c and HOMA-IR, FBG was independently and significantly associated with hypertension. The hazard ratio of participants with FBG ≥ 7.0 mmol/l was 1.79 compared with those with FBG < 5.6 mmol/l. Even among those with HbA1c < 6.5%, HOMA-IR < 2.5, body mass index < 25 kg/m2, age < 55 years old, blood pressure < 130/80 mm Hg or non- and moderate drinking, the results were similar. High 120-minute BG level and impaired insulin secretion did not increase the risk for hypertension., Conclusions: FBG was a predictable index for future incidence of hypertension in middle-aged Japanese men and women. This is the first study comparing predictive powers of indices of diabetes for the incidence of hypertension., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim was to investigate the risk of developing type 2 diabetes according to blood pressure (BP) levels and presence or absence of hypertensive treatment. This 5-year cohort study comprised 3508 Japanese adults aged 30-74 years without diabetes who had undergone a medical checkup including a 75-g oral glucose tolerance test (OGTT) between April 2008 and March 2009 at Saku Central Hospital. Participants receiving antihypertensive treatment were categorized into controlled hypertension ( < 140/90 mmHg) or uncontrolled hypertension ( ≥ 140/90 mmHg) groups. Participants not receiving antihypertensive treatment were categorized: optimal BP ( < 120/80 mmHg), normal BP (120-129/80-84 mmHg), high-normal BP (130-139/85-89 mmHg), grade I hypertension (140-159/90-99 mmHg), and grade II/III hypertension ( ≥ 160/100 mmHg). Hazard ratios and 95% confidence intervals for the incidence of type 2 diabetes as defined by the 75-g OGTT were estimated using multivariable-adjusted Cox proportional hazard models in reference to optimal BP. During an average of 4.4 years of follow-up, 295 participants developed type 2 diabetes. Those with high-normal BP, grade I hypertension, grade II/III hypertension, and uncontrolled hypertension were at significantly higher risk for developing type 2 diabetes, with hazard ratios (95% confidence intervals) of 1.53 (1.03-2.29), 1.53 (1.02-2.32), 2.19 (1.01-4.77), and 1.81 (1.10-2.99), respectively. In conclusion, compared with those with optimal BP, individuals with BP ≥ 130/85 mmHg not receiving antihypertensive treatment and uncontrolled hypertensives with BP ≥ 140/90 mmHg receiving antihypertensive treatment were at a significantly higher risk for developing type 2 diabetes.

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.

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.

We propose a highly wearable, upper-arm type, oscillometric-based blood pressure monitoring technology with low-stress. The low-stress is realized by new developments in the hardware and software design. In the hardware design, conventional armband; cuff, is almost halved in volume thanks to a flexible plastic core and a liquid bag which enhances the fitness and pressure uniformity over the arm. Reduced air bag volume enables smaller motor pump size and battery leading to a thinner, more compact and more wearable unified device. In the software design, a new prediction algorithm enabled to apply less stress (and less pain) on arm of the patient. Proof-of-concept experiments on volunteers show a high accuracy on both technologies. This paper mainly introduces hardware developments. The system is promising for less-painful and less-stressful 24-hour blood pressure monitoring in hypertension managements and related healthcare solutions.

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.)

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.

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.

Lindera strychnifolia (Tendai-Uyaku), a medicinal plant, has long been used for the treatment of cardiac, renal and rheumatic diseases in Japan. We investigated the effect of Lindera strychnifolia on systolic blood pressure, cardiac function, and plasma noradrenaline levels in rats. Spontaneously hypertensive rats (SHR) were given free access to water or extract solution of Lindera strychnifolia, which was extracted with a ratio of 10 g Lindera strychnifolia roots/20 ml water. Systolic blood pressure was measured by using a tail-cuf sphygmomanometer twice a week from 10 to 30 weeks of age, and compared to the age-matched Wistar Kyoto rats (WKY) as a control group. At 30 weeks of age, heart function was measured by echocardiography and blood samples were taken for detection of plasma noradrenaline levels, and rats were then sacrificed. Systolic blood pressure gradually increased from 10 to 30 weeks of age in the SHR group, while it did not change in the WKY group. In the Lindera-treated SHR group, the increase in systolic blood pressure was significantly attenuated from 21 to 30 weeks of age. Echocardiography showed a significant increase in ejection fraction in the Lindera-treated SHR group (60.4 +/- 7.8%) as compared to the SHR group (39.7 +/- 23.4%). Plasma noradrenaline levels were significantly decreased in Lindera-treated SHR group compared to the SHR group. These results suggest that Lindera strychnifolia has an anti-hypertensive effect and improves cardiac function in spontaneous hypertensive rats. These effects may be related to the decrease in plasma noradrenaline levels by Lindera strychnifolia.

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.

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.

1. In the present study, we investigated the role of endothelin ET(B) receptors in gender differences in the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene. 2. In wild-type rats, the elevation of systolic blood pressure (SBP) by DOCA-salt treatment for 4 weeks was extremely lower in females than in males, but this gender difference was partially attenuated in ovariectomized (OVX) animals. These alterations of SBP corresponded with vascular superoxide () production. 3. In homozygous (sl/sl) group, the SBP of male, intact female and OVX rats was markedly elevated by DOCA-salt treatment to the same extent, indicating that the gender difference in DOCA-salt-induced hypertension was abolished by the genetic ET(B) receptor deficiency. There were similar increases in the vascular endothelin (ET)-1 content in the three DOCA-salt-treated animal groups, but vascular production in male and OVX rats was much higher than that in intact females. 4. Daily oral administration of ABT-627, an ET(A) receptor antagonist, to sl/sl rats for 2 weeks suppressed the DOCA-salt-induced hypertension more efficiently in intact female rats than in male animals. 5. Thus, vascular oxidative stress is related, at least in part, to differences in the development of DOCA-salt-induced hypertension between male and female rats, but this gender difference is abolished by the genetic ET(B) receptor deficiency, suggesting that ET(B) receptor-mediated vasoprotective actions contribute to the gender differences seen. In addition, in both sexes, vascular ET-1 overproduction and the ET(A) receptor-mediated action seem to be responsible for the enhanced susceptibility to DOCA-salt hypertension in genetic ET(B) receptor deficiency.

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.

NADPH oxidase plays an important role in vascular oxidative stress in hypertensive diseases. We evaluated whether NADPH oxidase-dependent superoxide (O(2)(-)) production is involved in the deoxycorticosterone acetate (DOCA)-salt-induced hypertension, using mice which are genetically deficient in gp91phox, an NADPH oxidase subunit protein (gp91(-/-) mice). Two weeks after the DOCA-salt treatment, systolic blood pressure was significantly elevated in wild-type mice, but not in gp91(-/-) mice. After a 5-week treatment period, wild-type mice developed high blood pressure, with a systolic blood pressure of 127 +/- 3 mm Hg, compared with 107 +/- 4 mm Hg in gp91(-/-) mice. Aortic O(2)(-) production in wild-type DOCA-salt-treated mice was significantly higher than that in wild-type sham mice, whereas there were no significant differences in aortic O(2)(-) production between gp91(-/-) DOCA-salt-treated and sham mice. These findings suggest that vascular O(2)(-) overproduction via gp91phox-containing NADPH oxidase is one of the crucial factors in the development of DOCA-salt-induced hypertension.

Purpose: To examine the relationship of gender, cigarette smoking, and a history of hypertension to the risk of aneurysmal subarachnoid hemorrhage (SAH), using a case-control study., Methods: Case subjects consisted of a consecutive series of 201 patients with spontaneous SAH with aneurysm(s) confirmed by angiography and/or CT scan. One hospital and one community control subject was matched to each case by gender and age (+/- 2 years). Multiple conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) adjusted for potential confounders., Results: Current smoking and a history of hypertension were each significantly associated with an increased risk of subarachnoid hemorrhage for men and women combined. There was also a non-significant trend towards synergism between these two factors with respect to an increased risk of subarachnoid hemorrhage for each gender separately and both combined. A significantly increased risk was observed for a history of hypertension (adjusted OR, 3.5; 95% CI, 1.2-14.7) among men, for current smoking alone (adjusted OR, 2.9; 95% CI, 1.1-7.7), and a history of hypertension alone (adjusted OR, 2.6; 95% CI, 1.4-5.1) among women., Conclusions: Trends towards gender differences and synergism emerged in the relationship of cigarette smoking and a history of hypertension of the risk of SAH provides useful information for targeting individuals/populations in programs for the primary prevention of SAH by gender.

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.

We attempted to evaluate familial aggregation and coaggregation of history of hypertension and stroke. Past and family history of hypertension and stroke for 83 089 probands and their relatives were obtained from a data set for the Japan Collaborative Cohort Study for Evaluation of Cancer Risk sponsored by the Ministry of Education (JACC Study), which was initiated from 1988 to 1990. First, evaluation was performed for familial aggregation of each of two disorders using ordinal logistic regression of the generalized estimation equations (GEE) to account for dependence of observations within families. Secondly, in order to evaluate the familial congregation of the history of hypertension and stroke, a GEE-based multivariate probed predictive model was applied. After adjusting for the proband's age, level of obesity, smoking status, drinking status, habitation area, and the gender and type of the relatives, the estimated odds ratios for the intraindividual clustering and familial aggregation of the disease history showed statistically significant relationships. In addition, the history of the two disorders showed a significant relationship in terms of familial coaggregation independently of the aggregation of each disorder itself. Our results confirmed that hypertension and stroke coaggregate strongly within families through possible effects of genetic factors, which, alone or in conjunction with environmental factors, influence susceptibility to both hypertension and stroke.

Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.

Background: Hypertension complicated with pregnancy is a major cause of maternal and fetal mortality, but its pathophysiology is unclear., Objective: To investigate the pressor response to angiotensin II (Ang II) and the involvement of the Ang II degrading protease, aminopeptidase A, in spontaneously hypertensive rats (SHRs)., Design: Pregnant SHRs and Wistar-Kyoto (WKY) rats were studied. Angiotensin II (200 ng/kg per min) or saline was infused by osmotic pump from day of 15 gestation, and caesarean section was performed at day 20 of gestation. Blood pressure during pregnancy, weight of placentas and pups at caesarean section, and aminopeptidase A activity in placenta and renal cortex were measured., Results: Ang II treatment induced increases in blood pressure that were greater in non-pregnant WKY rats than those in pregnant WKY rats, pregnant SHRs, and non-pregnant SHRs. Renal aminopeptidase A activity in SHRs was significantly lower than that in WKY rats. Renal aminopeptidase A activity in pregnant SHRs was significantly greater than that in non-pregnant SHRs, but there was no significant increase in pregnant WKY rats. Placental aminopeptidase A activity in SHRs was greater than that in WKY rats. Placental aminopeptidase A activity in WKY rats was increased by Ang II, but was not increased in SHRs. Weights of placentas and pups were significantly lower in SHRs than in WKY rats., Conclusions: Renal aminopeptidase A may be involved in the development of hypertension and the regulation of blood pressure in SHRs. Placental aminopeptidase A may be upregulated in response to fetal stress in pregnant SHRs.

Pioneer studies have proposed that multiple metabolic abnormalities, such as insulin resistance, increased Na(+)-H(+) exchanger activity and abnormal intracellular calcium homeostasis, are frequently associated with a subset of essential hypertensive patients with low plasma renin activity (PRA). However, it is unclear whether insulin resistance is related to the low renin status in the very early phase of genetical hypertension. Besides, there is controversy on the subject of the in vivo effect of acute hyperinsulinaemia on sodium-related factors. We investigated the relationship between sodium-related parameters and insulin sensitivity, and the effects of euglycaemic hyperinsulinaemia on cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) levels in 17 young, lean, normotensive male subjects, who displayed extreme predispositions for the development of hypertension. PRA was significantly lower in the positive than in the negative family history group (P < 0.05). Insulin sensitivity (M-value) was correlated with PRA before euglycaemic hyperinsulinaemic clamping (r = 0.577, P < 0.05), and was also inversely correlated with fractional excretion of sodium (FE(Na)) before clamping (r = -0.51, P < 0.05). Euglycaemic hyperinsulinaemia significantly decreased PRA (P < 0.0001) and increased cGMP (P < 0.05) and ANP levels (P < 0.01). In conclusion, insulin sensitivity may be partially determined by PRA levels and FE(Na) before clamping in young, lean, normotensive male subjects. Acute euglycaemic hyperinsulinaemia decreases PRA, and increases cGMP and ANP levels from the fasting condition.

Insulin resistance is known to be closely related to essential hypertension. It has been hypothesized that abnormal calcium homeostasis both at the cellular level and in the whole body plays a substantial role in hypertension associated with insulin resistance. We attempted to determine the relationships among insulin sensitivity, blood pressure (BP), body mass index (BMI), and calcium-related parameters in young, lean, normotensive male subjects with extreme susceptibilities to hypertension, and to investigate the effects of euglycemic hyperinsulinemia on calcium-related parameters. Seven young, lean, normotensive male subjects with family histories of essential hypertension and 10 age-matched controls without any parental cardiovascular events were enrolled. Insulin sensitivity measurement by the euglycemic hyperinsulinemic clamp technique and a 75-g oral glucose tolerance test were performed. Calcium-related parameters, including intracellular Ca2+ levels in platelets, were measured simultaneously. Diastolic BP was inversely correlated with insulin sensitivity in vivo (M-value). Insulin sensitivity was inversely correlated with BMI and with intracellular Ca2+ in platelets. In the multivariate stepwise regression analysis using both diastolic BP and insulin sensitivity as dependent variables, BMI was found to be a determinant independent variable. Euglycemic hyperinsulinemia decreased intact parathyroid hormone levels and increased fractional excretion of calcium. In conclusion, BMI rather than a family history of hypertension plays a determinant role on the regulation of diastolic BP and insulin sensitivity even in young, lean, normotensive male subjects with extreme predispositions for the development of hypertension. Hyperinsulinemia decreased intact parathyroid hormone levels and increased fractional excretion of calcium.

Objective: To investigate the effects of oestrogen supplementation after ovariectomy on systolic blood pressure and platelet aggregation on different sodium content diet in the female Dahl salt-sensitive rats., Methods: At 12 weeks of age, rats were ovariectomized or sham-operated and were fed either a high NaCl (8%) or low NaCl (0.3%) diet Ovariectomized rats were treated with either 17beta-oestradiol or placebo for 8 weeks, whereas sham-operated rats received placebo alone. After 8 weeks, the systolic blood pressure and platelet aggregation were measured and analysed by two-way analysis of variance., Results: The systolic blood pressure of ovariectomized rats was significantly higher than that of sham-operated rats, and this increase in systolic blood pressure was suppressed by oestrogen supplementation. Systolic blood pressure was inversely correlated with plasma 17beta-oestradiol levels (r= -0.77, P< 0.01) and with the uterus weight to body weight ratio (r = -0.47, P < 0.01). Platelet aggregation was significantly enhanced by salt loading. Salt loading and female hormonal manipulation significantly interacted on platelet aggregation. Only in Dahl salt-sensitive rats fed a low sodium diet, ovariectomy increased platelet aggregation, whereas hormone replacement did not improve it. In Dahl salt-sensitive rats fed a high sodium diet, hormone replacement reduced platelet aggregation., Conclusions: Oestrogen replacement suppresses the development of hypertension and attenuates platelet aggregatory function in the salt-loaded ovariectomized Dahl salt-sensitive rats. It has a potential to inhibit the atherosclerotic process in postmenopausal hypertension.

Epistasis used to be considered an obstacle in mapping quantitative trait loci (QTL) despite its significance. Numerous epistases have proved to be involved in quantitative genetics. We established a backcross model that demonstrates a major QTL for hypertension (Ht). Seventy-eight backcrossed rats (BC), derived from spontaneously hypertensive rats (SHR) and normotensive Fischer 344 rats, showed bimodal distribution of systolic blood pressure (BP) values and a phenotypic segregation ratio consistent with 1:1. In this backcross analysis, sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (Serca) II heterozygotes showed widespread bimodality in frequency distribution of BP values and obviously demonstrated Ht. First, in genome-wide screening, Mapmaker/QTL analysis mapped Ht at a locus between D1Mgh8 and D1Mit4 near Sa in all 78 BC. The peak logarithm of the odds (LOD) score reached 5.3. Second, Serca II heterozygous and homozygous BC were analyzed separately using Mapmaker/QTL. In the 35 Serca II heterozygous BC, the peak LOD score was 3.8 at the same locus whereas it did not reach statistical significance in the 43 Serca II homozygotes. Third, to map Ht efficiently, we selected 18 Serca II heterozygous BC with 9 highest and 9 lowest BP values. In these 18 BC, the peak LOD score reached 8.1. In 17 of the 18, D1Mgh8 genotypes (homo or hetero) qualitatively cosegregated with BP phenotypes (high or low) (P < 0.0001, by chi-square analysis). In conclusion, selective genotyping with epistasis can be utilized for a major QTL mapping near Sa on chromosome 1 in SHR.

Our purpose was to determine the effect of ovariectomy on intracellular Ca2+ mobilization and platelet aggregation in sodium induced hypertension. At the age of 12 weeks ovariectomy or sham operation was performed in female Dahl-Iwai salt sensitive rats on a 0.3% NaCl diet. Four weeks later we assessed the effects of ovariectomy and an 8% NaCl diet on agonist induced intracellular Ca2+ mobilization in fura-2 loaded platelets and platelet aggregation. Ovariectomy enhanced the increase of systolic blood pressure and heart to body weight ratio on an 8% NaCl diet. However, thrombin evoked intracellular Ca2+ was not correlated with systolic blood pressure (r = -0.338, P = .17), and was lowered by sodium loading and ovariectomy (360+/-23 to 285+/-9, 296+/-10 nmol/L, P < .05). Furthermore, the ionomycin induced intracellular calcium fraction in the absence of external Ca2+ that reflected internal Ca2+ discharge capacity was reduced in ovariectomized rats compared with sham operated rats on an 8% NaCl diet (648+/-15 v 768+/-35 nmol/L, P < .05). The internal Ca2+ discharge capacity was inversely correlated with systolic blood pressure (r = -0.506, P = .03). In addition to the decreased internal Ca2+ discharge capacity, intracellular Ca2+-independent platelet aggregation by phorbol 12-myristate 13-acetate, a protein kinase C activator, was significantly enhanced in hypertensive rats. We concluded that ovariectomy enhanced sodium induced hypertension associated with the decreased internal Ca2+ discharge capacity and increased platelet aggregation in Dahl-Iwai salt-sensitive rats.

Hypertension is characterized by a complex mode of inheritance, consisting of the accumulation and interaction of major and minor genes. The existence of a single major gene locus (ht) has been demonstrated in the backcross analysis of spontaneously hypertensive rats (SHR) and normotensive Donryu rats. Intracellular Ca2+ concentration ([Ca2+]i) determines the tonus of vascular smooth muscle. It has been hypothesized that abnormal Ca2+ transport is an inheritable trait with profound influence on the development of hypertension. Backcross analysis between SHR and Donryu rats was performed to demonstrate ht and to dissect polygenic hypertensive traits through ht and abnormal intracellular Ca2+ metabolism. Among the parental strains, systolic blood pressure and thrombin-stimulated [Ca2+]i in platelets were significantly greater in SHR than in Donryu and F1 rats. The backcrossed rats were distributed into two clusters on a scattergram of blood pressure versus [Ca2+]i, demonstrating the existence of ht. The blood pressure level was correlated with thrombin-stimulated [Ca2+]i in each cluster. Increased [Ca2+]i in platelets was not coinherited with ht and was considered to be a minor inheritable hypertensive trait discriminated from ht. Therefore, [Ca2+]i in platelets is an inadequate marker for searching ht.

A cosegregation analysis of sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (SERCA) II genotype, systolic blood pressure and platelet intracellular Ca2+ concentration was performed to dissect polygenic hypertensive traits in spontaneously hypertensive rats. Backcross analysis between spontaneously hypertensive rats and normotensive. Donryu rats demonstrated the existence of an inferred single major gene locus (ht). Thrombin-stimulated intraplatelet Ca2+ concentration was significantly higher in the SERCA II homozygotes than in the heterozygotes. The SERCA II genotype did not cosegregate with the blood pressure level. The SERCA II gene was assigned to rat chromosome 12. These results suggest that the SERCA II gene on rat chromosome 12 contributes to increased thrombin-stimulated intraplatelet Ca2+ concentration and that the SERCA II gene is not identical to ht.

To investigate the role of sodium in obesity induced hypertension, Wistar fatty rats (WFR) were employed. This rat has the following characteristics: (1) hyperglycemia, (2) hyperinsulinemia, and (3) hypertriglycemia. Four percent sodium chloride with constant amount of food intake was administered to these rats from 8 to 16 weeks. During this period, body wt, food intake, water consumption, urine volume, systolic blood pressure, urinary excretion of sodium and potassium, urinary albumin excretion, plasma sodium and potassium, and plasma glucose and immunoreactive insulin (IRI) were measured before, and twice more during eight weeks. No remarkable changes were observed in plasma glucose level during these periods between the two groups. On the other hand, in group 1 IRI significantly increased compared with group 2. Mean blood pressure was increased from 110 +/- 5 to 130 +/- 8 mm Hg (P < 0.01). To ascertain whether this salt sensitivity relates to the abnormalities in pressure-natriuresis responses, the pressure-natriuresis (P-N) was characterized. The P-N curve in WFR was shifted to the right and its slope was flattened compared to its control Wistar lean rats. In conclusion, an excess of dietary sodium intake may contribute to an elevation of blood pressure in Wistar fatty rat with hyperglycemia and hyperinsulinemia. This salt sensitivity may change the abnormal pressure-natriuresis responses.

Objective: To search for a genetic marker of the sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (SERCA) II gene in spontaneously hypertensive rats (SHRs) and to investigate differences in blood pressure and intracellular Ca2+ among some substrains of SHRs and Wistar-Kyoto (WKY) rats related to their SERCA II genotypes., Design and Methods: The coding region of the SERCA II gene was sequenced in SHRs. Blood pressure and intracellular Ca2+ concentration ([Ca2+]i) in platelets were measured in substrains of SHRs and WKY rats with different SERCA II genotypes., Results: A point mutation that provided restriction fragment length polymorphisms (RFLPs) by HindIII or Saul was found in the SERCA II gene. The polymerase chain reaction (PCR) products were digested by HindIII in SHR substrains and WKY-Kyoto rats, whereas they were digested by Saul in normotensive strains and SHR-Toho. Among SHR-Kyoto, SHR-Toho, WKY-Kyoto and WKY-Charles River, the substrains with the HindIII-digested SERCA II genotype showed slightly but significantly higher systolic blood pressure and augmented agonist-stimulated [Ca2+]i than those with the Saul-digested genotype., Conclusions: RFLPs were found in the SERCA II gene. In the substrain analysis of SHRs and WKY rats, higher blood pressure and increased [Ca2+]i were associated with the SERCA II genotype digested by HindIII. The SERCA II gene locus has the potential to contribute to the development of hypertension and abnormal intracellular Ca2+ metabolism in SHRs. These RFLPs in the SERCA II gene should be a useful genetic marker.

1. Blood pressure and Ca2+ mobilization were significantly greater in SHR than in Donryu and F1 rats. 2. Backcross linkage analysis between spontaneously hypertensive rats and normotensive Donryu rats was performed to dissect polygenic hypertensive traits and to detect the existence of a single 'major gene'. 3. Cluster and discriminant analysis of a scattergram of blood pressure versus Ca2+ mobilization classified the backcrossed rats into two groups. The two groups were referred to the higher group and the lower group with regard to their relative blood pressure values. 4. Blood pressure was correlated with Ca2+ mobilization in each group; the correlation coefficients were 0.41 for the higher group (P < 0.01) and 0.71 for the lower group (P < 0.0001).

1. To reveal the mechanism responsible for the increase in blood pressure (BP) response to high salt intake in salt-sensitive essential hypertensives, pressor responses to angiotensin II and norepinephrine on high and low salt diet, influence of high salt intake on calcium metabolism and insulin sensitivity were studied in essential hypertensive and in normotensive subjects with or without family history of hypertension. 2. Pressor responses to angiotensin II and norepinephrine were significantly increased in salt-sensitive essential hypertensives irrespective of high or low salt diet. 3. In normotensive subjects with positive family history, high salt diet elevated BP in association with an increase in urinary calcium excretion. This observation, however, was not shared by the normotensive subjects with negative family history of hypertension. In the normotensive subjects with positive family history of hypertension, the cytosolic calcium concentration in platelets was significantly higher than in those with negative family history. A significant correlation between the cytosolic calcium concentration and elevation of BP was also observed. 4. In normotensive subjects with family history of hypertension, insulin sensitivity was decreased and correlated negatively with the cytosolic calcium concentration. 5. These results suggest that in salt-sensitive essential hypertensives increased pressor responses to angiotensin and norepinephrine and elevation of BP as well as insulin resistance may result from inherited abnormalities of intracellular calcium metabolism.

Oral calcium supplementation is reported to have phosphate-binding and antihypertensive effects. Since both phosphate binders and antihypertensive agents are reported to attenuate renal injury, we studied the effect of oral calcium carbonate (CaCO3) administration on the course of renal deterioration using doxorubicin-induced renal failure in rats treated with deoxycorticosterone acetate and salt for 10 weeks. Rats were divided into four groups: the CaCO3 (6.0 g/kg/d) group (n = 12), the aluminum hydroxide (Al(OH)3; 6.0 g/kg/d) group (n = 11, as a phosphate-binder control), the hydralazine (10 mg/kg/d) group (n = 11, as an antihypertensive control), and the control group (n = 12). All agents were given as a mixed chow diet. Blood pressure and urinary protein excretion progressively increased in the control rats. CaCO3 and hydralazine lowered blood pressure, but Al(OH)3 did not (185 +/- 4 mm Hg, control; 160 +/- 5 mm Hg, CaCO3; 171 +/- 8 mm Hg, Al(OH)3; 156 +/- 5 mm Hg, hydralazine at week 10). Proteinuria was reduced in the rats treated with CaCO3 and Al(OH)3 compared with those without the treatment (986 +/- 86 mg/d, control; 551 +/- 54 mg/d, CaCO3; 527 +/- 31 mg/d, Al(OH)3; and 955 +/- 68 mg/d, hydralazine at week 10). Serum phosphate concentration and calcium phosphate products also were significantly lower in both the CaCO3 and Al(OH)3 groups than in the control group. At week 10, increased serum urea nitrogen, impaired renal function, and glomerular sclerosis present in the control group were significantly attenuated in both in the CaCO3 and Al(OH)3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the effect of dietary calcium (Ca) and salt on blood pressure and vascular reactivity, 5-week-old male spontaneously hypertensive rats were placed on control (1% Ca diet+tap water), high Na (1% NaCl administered in drinking fluid), low Ca (0.2% Ca diet), and low Ca+high Na intake for 3 weeks (n = 8-10). During the observation period, systolic blood pressure increased in all groups, but the increase was markedly enhanced in the low Ca+high Na group. There were no significant differences in body weight and serum electrolytes. On high Na intakes, urine volume and urinary Na excretion increased and plasma renin activity and aldosterone concentration were suppressed, whereas Ca restriction did not affect these values. The dose-response curves of mesenteric arterial beds for in vitro contraction to norepinephrine (NE) were not affected by dietary manipulations. However, the time from maximum contraction to return to baseline levels of contractility by 10(-4) M NE was significantly prolonged in the low Ca+high Na group. These results indicate that Ca restriction accelerates salt-induced hypertension in young spontaneously hypertensive rats, and the cellular impairment in vascular smooth muscle might, at least in part, participate in the enhanced blood pressure elevation under this condition.

Objectives: To determine whether insulin sensitivity is impaired in normotensive offspring of essential hypertensives and to investigate how it relates to disturbed calcium metabolism., Design: In 10 young lean, normotensive subjects with family histories of essential hypertension and in 10 age-matched controls we investigated insulin sensitivity by the euglycaemic hyperinsulinaemic clamp technique, and 75-g oral glucose tolerance test (GTT). We simultaneously measured calcium-related factors, including the intracellular calcium concentration in platelets., Results: Insulin-induced glucose uptake was significantly impaired in subjects with positive compared with in subjects with negative family history of essential hypertension. Intracellular calcium concentration was significantly higher in subjects with positive than in those with negative family history. Insulin sensitivity was inversely correlated with intracellular calcium concentration (r = -0.56; P < 0.05). Those who showed a higher intracellular calcium concentration had impaired insulin sensitivity. Oral GTT results were normal in both groups., Conclusion: Impaired insulin sensitivity and disturbed calcium metabolism exist before the onset of hypertension. Insulin sensitivity correlates inversely with intracellular calcium concentration. These findings suggest that the association of the impaired insulin sensitivity and disturbed calcium metabolism may contribute to the development of hypertension.

To assess a possible heritability of a disturbed calcium metabolism in relation to blood pressure regulation, 28 young normotensive offspring of either hypertensive or normotensive parents were studied while administered a defined diet with daily sodium chloride of 6 and 20 g/day for 7 days each. Before the high salt diet was begun, the cytosolic calcium concentration ([Ca2+]i) in platelets was elevated in offspring of hypertensive parents, whereas serum electrolytes, plasma renin activity, plasma catecholamines, and 24-hour urinary excretion of sodium and calcium showed no difference between the two groups. On exposure to a high salt diet, the mean blood pressure increased (from 80 +/- 2 to 85 +/- 2 mm Hg, p less than 0.05) in offspring of hypertensive parents. These changes in mean blood pressure were positively correlated with the basal platelet [Ca2+]i (r = 0.61, p less than 0.01), whereas [Ca2+]i did not demonstrate any significant changes. When the subjects were administered the high salt diet, plasma ionized calcium decreased (from 2.37 to 2.21 meq/l, p less than 0.05) and 1,25-dihydroxyvitamin D3 increased (from 32.7 to 40.8 pg/ml, p less than 0.05) with a transient relative hypercalciuria in offspring of hypertensive parents. This increase of 1,25-dihydroxyvitamin D3 was significantly correlated with the changes in mean blood pressure (r = 0.62, p less than 0.01). Disturbed intraplatelet and systemic calcium metabolism may be of predictive value in the development of hypertension.

1. To investigate the role of cytosolic calcium in salt-induced hypertension, a high salt diet was given to young normotensive subjects with or without a family history of hypertension. 2. A high salt diet raised blood pressure significantly in normotensive subjects with a family history compared with the age and gender matched subjects without a predisposition to hypertension. 3. Platelet cytosolic calcium was increased in predisposed subjects in a control period before salt intake. 4. A positive correlation was observed between the changes in mean blood pressure and cytosolic calcium before high salt intake, although salt loading did not induce any significant change in cytosolic calcium. 5. These results suggest that cytosolic calcium plays a role in elevation of blood pressure induced by salt loading in subjects with a family history of hypertension.