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The Japanese hypertension guidelines report that essential hypertension is detected in 1-3% of upper elementary and high school students during blood pressure (BP) screenings. Hypertension in these age groups is an emerging public health concern mainly attributed to the rising rate of pediatric obesity. Considering the existence of BP tracking phenomenon, early preventive education and instruction are necessary, especially for male students with moderately elevated BP showing a tendency toward obesity, despite the low prevalence of hypertension in high school students. Students with a positive family history of hypertension and those born with low birth weight need the same measures. Lifestyle habits, such as increased alcohol intake, dramatically change once students begin university; thus, early education and instruction regarding the factors influencing BP are necessary. In particular, for male students with higher BP during high school, caution regarding increased body weight is required irrespective of their level of obesity. Young adults aged <40 years should be educated about the association between body weight and hypertension. Particular caution surrounding lifestyle habits, including drinking and smoking, is warranted in male hypertensive subjects because hypertension at a young age is strongly associated with obesity. BP monitoring and the management of obesity should be considered efficient approaches to the detection and treatment of hypertension. For the lifetime prevention of hypertension, it is essential to be aware of one's health status and learn about healthy lifestyles beginning in childhood. BP measurement may be an appropriate means to achieve this goal.

We compared three benidipine-based regimens-that is, benidipine plus angiotensin receptor blocker (ARB), β-blocker (BB) or thiazide-and found that the benidipine-BB combination was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (<140/90 mm Hg) on the cardiovascular outcomes among the three benidipine-based treatment groups in the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. This sub-analysis included 3001 subjects to evaluate the achievement of target BP at a minimum of three points at 6-month intervals of clinical BP measurements during the study period. After randomization, the patients were categorized into two groups on the basis of achieved on-treatment target BP: a good control (GC) group achieving a BP⩾66.7% of the target and a poor control (PC) group with a BP <66.6% of the target. For each of the two control groups, outcomes were compared among the three treatment groups. The event rates for cardiovascular composite endpoints, stroke and hard cardiovascular events were higher in the PC group than the GC group (P=0.041, P=0.042 and P=0.038, respectively). Within the PC group, hazard ratios for the incidence of cardiovascular events were lower in the benidipine-thiazide group than in the benidipine-BB group (composite cardiovascular events: 2.04, P=0.033; stroke: 4.14, P=0.005; and hard cardiovascular events: 3.52, P=0.009). Within the GC group, the incidence of cardiovascular events was not different among the three treatment regimens. The benidipine-thiazide combination may provide better cardiovascular outcomes than the benidipine-BB combination even in patients with poor BP control.

Our aim was to assess optimal on-treatment blood pressure (BP) at which cardiovascular disease (CVD) and all-cause mortality risks are minimized in Japanese older adults with isolated systolic hypertension. We used data from the VALISH study (Valsartan in Elderly Isolated Systolic Hypertension) that recruited older adults (n=3035; mean age, 76 years) with systolic BP (SBP) of ≥160 mm Hg and diastolic BP of <90 mm Hg. Patients were treated by valsartan. Patients were also categorized into 3 groups based on achieved on-treatment SBP of <130 mm Hg (n=317), 130 to <145 mm Hg (n=2025), or ≥145 mm Hg (n=693). The primary outcome was composite CVD (coronary heart disease, stroke, heart failure, cardiovascular deaths, other vascular diseases, and kidney diseases) with secondary outcome being all-cause mortality. Cox proportional hazards models were used to assess the CVD risk for each group. Over a median 3-year follow-up (8022 person-years), 93 CVD events and 52 deaths occurred. Using the on-treatment SBP of 130 to <145 mm Hg as reference stratum, the multivariable-adjusted hazard ratios and 95% confidence intervals of CVD and all-cause mortality risks for those with SBP<130 mm Hg were 2.08 (1.12-3.83) and 2.09 (0.93-4.71) and for those with SBP≥145 mm Hg were 2.29 (1.44-3.62) and 2.51 (1.35-4.66), respectively. On-treatment diastolic BP yielded no relationships with CVD or all-cause mortality risk. In conclusion, among Japanese older adults with isolated systolic hypertension, SBP in the range between 130 and 144 mm Hg was associated with minimal adverse outcomes and a reduction in CVD and all-cause mortality. The BP range will need to be confirmed in randomized controlled trials., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00151229., (© 2017 American Heart Association, Inc.)

Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a β-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), β-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; β-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine-β-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine-β-blocker combination.

Objective: The aims of this subanalysis of the COLM trial [NCT00454662] were to compare visit-to-visit variability (VVV) of blood pressure (BP) between age groups and between two treatment combinations, that is, the angiotensin II receptor blocker, olmesartan combined with a calcium channel blocker (CCB), or a diuretic and to investigate the effect of VVV of BP on cardiovascular events in elderly hypertensive patients., Methods: Hypertensive patients ages 65-84 years with a history of and/or risk factors for cardiovascular disease were randomized to receive treatment with olmesartan along with either a CCB or a diuretic for at least 3 years. This subanalysis comprised 4876 patients who had their office BP measured at least three occasions (median nine occasions) during the follow-up period. VVV of BP was defined by several metrics including the within-individual standard deviation of every visit during the follow-up period., Results: VVV of SBP was larger in the very elderly group (75-84 years) than in the elderly group (65-74 years). VVV of SBP was smaller in the olmesartan along with CCB group than in the olmesartan along with diuretic group, especially in very elderly patients and also isolated systolic hypertensive patients. The incidence rate of primary endpoint increased along with an increment in the SD of SBP in all of the age and treatment groups., Conclusion: VVV of SBP may mediate the preferable effect of combination of angiotensin II receptor blocker along with CCB on cardiovascular events in the very elderly and also isolated systolic hypertensive patients.

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; <140/90 mm Hg). We further evaluated the efficacy and safety of these combination therapies in older (65 years) and younger (<65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (153365 years old and 1760 <65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a β-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P=0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08-6.96; β-blocker vs. thiazide, P=0.022) for fatal and non-fatal stroke, and 2.47 (1.03-5.91; β-blocker vs. ARB, P=0.043) for new-onset diabetes. Thus, benidipine combined with an ARB, a β-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.

Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy.

Background: The impact of the metabolic syndrome (MS) on cardiovascular events in elderly subjects has not been clarified. We hypothesized that the impact differs between patients with and without strictly controlled blood pressure (BP) and also between early elderly (<75 years) and late (≥75 years) elderly patients., Methods: Elderly hypertensive patients (65-85 years old) were randomly assigned to strict (target systolic BP <140 mm Hg) or mild (140-159 mm Hg) BP target, and were treated for 2 years with efonidipine-based regimen. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, except for the use of body mass index (BMI) ≥25 kg/m(2) instead of waist circumference. Primary endpoint was combined incidence of cardiovascular and renal events. Data were obtained from 2,865 patients., Results: The prevalence of MS was 31.4%. The incidence of primary endpoint in patients with and without MS was 4.0% and 3.1%, respectively. MS was a significant risk factor for cardiovascular events in patients <75 years old (adjusted hazard ratio (HR) 2.17, P = 0.01), but not in patients ≥75 years old (adjusted HR 0.98, P = 0.94). In patients with MS, the event rate was significantly lower with strict treatment than with mild treatment among patients aged <75 years (P = 0.0006) but not in those aged ≥75 years (P = 0.82)., Conclusions: MS was associated with cardiovascular risk in elderly hypertensive patients <75 years old, and strict BP control was beneficial for those with MS. However, MS and intensive control of BP may have little effect on cardiovascular events in elderly patients ≥75 years old.

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (<140 mm Hg) is superior to moderate blood pressure control (> or =140 mm Hg to <150 mm Hg) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension. We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension (sitting blood pressure 160 to 199 mm Hg) into 2 groups, according to strict or moderate blood pressure treatment. A composite of cardiovascular events was evaluated for > or =2 years. The strict control (1545 patients) and moderate control (1534 patients) groups were well matched (mean age: 76.1 years; mean blood pressure: 169.5/81.5 mm Hg). Median follow-up was 3.07 years. At 3 years, blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg, respectively. The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg. The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group (hazard ratio: 0.89; [95% CI: 0.60 to 1.34]; P=0.38). In summary, blood pressure targets of <140 mm Hg are safely achievable in relatively healthy patients > or = 70 years of age with isolated systolic hypertension, although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets.

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

Background: In a previously reported randomized, double-blind, parallel-group study of the efficacy and tolerability of olmesartan medoxomil (OLM) and azelnidipine (AZL) combination therapy compared with monotherapy with each agent in Japanese patients with essential hypertension (the REZALT study), the use of a combination of OLM, an angiotensin II receptor blocker, plus AZL, a dihydropyridine calcium channel blocker, was associated with significantly greater reductions in office sitting blood pressure (BP) and 24-hour ambulatory BP compared with monotherapy with either agent, and was well tolerated., Objective: This article reports the results from an a priori planned analysis and post hoc analyses of the diurnal BP and pulse rate (PR) profiles of OLM/AZL versus monotherapy with either agent from the REZALT study., Methods: Male and female Japanese outpatients with essential hypertension were eligible if they met the following inclusion criteria: age > or = 20 years; systolic BP (SBP) > or = 140 to <180 mm Hg and diastolic BP (DBP) > or = 90 to <110 mm Hg; and 24-hour ambulatory SBP/DBP > or = 135/> or = 80 mm Hg. Patients were randomly assigned to receive OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM 20 mg, or AZL 16 mg, once daily for 12 weeks. The effectiveness of the treatments was assessed using 24-hour ambulatory BP monitoring (ABPM) and PR, analyzed by time period (BP and PR, 24 hours, daytime [7 AM-<10 PM], nighttime [10 PM-<7 AM], and early morning [6 AM-<9 AM]; PR, morning [6 AM -<11 AM]) and dipping status at baseline (dippers [(Daytime BP - Nighttime BP)/Daytime BP > or = 10%] or nondippers [(Daytime BP - Nighttime BP)/Daytime BP <10%])., Results: A total of 867 patients were enrolled, and 862 randomized patients were included in the full analysis set (590 men, 272 women; mean age, 56.6 years). A total of 839 patients had assessable ABPM data (213, 211, 206, and 209 patients in the OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM, and AZL groups, respectively). No clinically significant between-group differences were observed in baseline demographic and clinical characteristics. Combination therapy was associated with significantly greater antihypertensive effects on 24-hour ABPM compared with either monotherapy in all of the time periods, as follows: SBP/DBP reductions with OLM/AZL 20/16 mg in the daytime, nighttime, and early morning were -22.6/-14.1, -21.2/-12.5, and -20.6/-11.9 mm Hg, respectively (all, P < 0.05 vs the other 3 treatment groups). The SBP/DBP reductions with OLM/AZL 10/8 mg (daytime, -18.2/-11.0 mm Hg; nighttime, -18.1/-10.0 mm Hg; and early morning, -15.6/-9.3 mm Hg) were also significantly greater than with OLM 20 mg (-11.8/-6.7, -12.8/-7.2, and -11.0/ -6.9 mm Hg, respectively; all, P < 0.01) and AZL 16 mg (-13.1/-7.8, -10.2/-5.5, and -9.9/-6.1 mm Hg; all, P < 0.001) in all of the time periods. The antihypertensive effects associated with OLM/AZL 10/8 mg or 20/16 mg were significantly greater than those with monotherapies regardless of dipping pattern at baseline (all, P < 0.05) in all of the time periods, with the exception of nighttime reduction with OLM/AZL 10/8 mg versus OLM in dippers. The numbers of patients who had any increase in BP were 12/213 (5.6%) with OLM/AZL 10/8 mg, 13/211 (6.2%) with OLM/AZL 20/16 mg, 35/206 (17.0%) with OLM, and 36/209 (17.2%) with AZL. The AZL-containing regimens were associated with reduced morning PR (mean [95% CI] changes from baseline to week 12: -1.5 beats/min [-2.5 to -0.4] with OLM/AZL 10/8 mg, -2.1 beats/min [-3.0 to -1.1] with OLM/AZL 20/16 mg, 0.4 beat/min [-0.5 to 1.3] with OLM, and -1.9 beats/min [-2.8 to -1.0] with AZL)., Conclusion: In this study in Japanese patients with essential hypertension, the reductions in daytime, nighttime, and early-morning BP assessed using 24-hour ABPM were significantly greater with combination OLM/AZL than with either monotherapy, regardless of dipping pattern at baseline. Japan Pharmaceutical Information Center registration number: JapicCTI-060286., (Copyright 2010 Excerpta Medica Inc. All rights reserved.)

Various guidelines for hypertension specify that the target blood pressure (BP) should be below 140/90 mm Hg and that strict control is recommended for patients with cardiovascular risk factors. We examined the relationship between the achieved BP and the incidence of cardiovascular events in hypertensive patients with complications as a sub-analysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial. A total of 4703 patients were evaluated for efficacy in the CASE-J trial. In this sub-analysis, 4553 patients had at least one follow-up visit without any cardiovascular events. We examined the relationship between the achieved BP and cardiovascular events in hypertensive patients with type II diabetes mellitus (DM), chronic kidney disease (CKD) or left ventricular hypertrophy (LVH) at baseline. Possible baseline confounders were adjusted by using the multiple Cox regression model. A higher achieved BP was associated with an increased risk of cardiovascular events in hypertensive patients with complications (DM, CKD or LVH). In patients with LVH, who achieved systolic/diastolic BP (SBP/DBP) <130/75-79 mm Hg, the risk of cardiovascular events was reduced to the same level of SBP/DBP <130/75-79 mm Hg in those without LVH. However, the risks of cardiovascular events in patients with DM or CKD, who achieved SBP/DBP <130/75-79 mm Hg, were still significantly higher than in those without DM or CKD. In conclusion, this study extended the significance of BP control in hypertensive patients especially with complications. Further investigation in a large-scale clinical trial is needed to determine the optimal target BP for LVH patients.

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

Home blood pressure (HBP) is usually measured in the morning and evening, but the evening HBP tends to be influenced by an individual's behavior pattern, such as bathing and drinking, which are often seen in the Japanese. In this study, in order to elucidate the influence of nighttime drinking on the evening and next morning HBP and heart rate (HR), HBP measurement was performed in Japanese normotensives under conditions in which the influence of bathing was minimized. Among 700 registered volunteers, 245 normotensives (189 male, 56 female, mean age; 35.8 +/- 0.5 years old) whose data consisted of a combination of drinking and non-drinking on workdays were selected. A semi-automatic device was lent to all participants, and they were asked to perform triplicate morning and evening measurements on seven consecutive days between October 16, 2002, and November 13, 2002. The differences in evening HBP and HR between the drinking and non-drinking days were calculated, as were the differences in the next morning HBP and HR. Only data of evening HBP measured at least 30 min after bathing were accepted. Evening SBP and DBP on drinking days were significantly lower (2.5 +/- 0.5 mmHg, 3.1 +/- 0.5 mmHg) than those on non-drinking days. On the other hand, evening HR on drinking days was significantly higher (7.7 +/- 0.8 b.p.m.) than that on non-drinking days. Although there was no difference in morning SBP after days with and without drinking, morning DBP the day after drinking was slightly (0.8 +/- 0.3 mmHg) but significantly lower than that the day after non-drinking. Morning HR the day after drinking was significantly higher (2.4 +/- 0.4 b.p.m.) than that after non-drinking. Because nighttime drinking influenced the evening HBP even in normotensives, it was suggested that morning HBP could give more stable values than evening HBP in Japanese people.

Few reports provide clear guidelines on how home blood pressure (HBP) should be measured in practice. In this study, we evaluated the influence of repeated HBP measurements on one occasion, and the difference between the 1st and 2nd day and between workdays and nonworkdays. The subjects (468 male, 232 female; mean age 41 years) were recruited from one company. HBP was measured with a semiautomatic device (Omron HEM-759P). Subjects were instructed to perform triplicate morning (m) and evening (e) measurements on 7 consecutive days. HBP tended to decrease during repeated measurements: systolic blood pressure (SBP) was significantly higher the 1st time than the 2nd time and 3rd time. There was no difference in diastolic blood pressure (DBP) between the 1st and 2nd time, but the value the 3rd time was significantly lower than the 1st and 2nd time. Both mHBP and eHBP on the 1st day were significantly higher than those on the 2nd day. mHBP was higher on the 1st workday than on nonworkdays, but the difference was less than 1 mmHg and there was no significant difference. Since there were significant differences in HBP during repeated measurements and between the 1st and 2nd day, which value to adopt as HBP needs to be discussed. Whether HBP was measured on a workday or a nonworkday seemed to have little influence on the HBP values obtained.

Although lowering blood pressure (BP) reduces aortic stiffness, achieving the recommended BP goal can be difficult. Recent studies have shown that short-term use of statins can reduce BP significantly. To determine the long-term effects of statins on BP and aortic stiffness, a single-blind randomized prospective study was performed on 85 hyperlipidaemic hypertensive patients whose BP was insufficiently controlled by antihypertensive therapy. Every 3 months, aortic stiffness was assessed by measuring pulse wave velocity (PWV). Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a nonstatin antihyperlipidaemic drug. No significant differences in patient characteristics, kinds of antihypertensive drugs, BP, ankle brachial index, PWV, or serum lipid, creatinine, or C-reactive protein levels were found between the four groups at the start of the study. During the 12-month treatment period, PWV did not change in the pravastatin group or nonstatin group, but it was transiently reduced in the simvastatin group and significantly decreased in the fluvastatin group, even though the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidaemic drugs significantly decreased serum cholesterol levels without affecting BP, ankle brachial index, or serum triglyceride levels. The C-reactive protein serum levels decreased significantly in the three statin groups but not in the nonstatin group. These results suggest that long-term use of fluvastatin by hyperlipidaemic hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on BP.

Background: Aortic stiffness is assessed by pulse wave velocity (PWV) and predicts the cardiovascular morbidity and mortality of hypertensive patients. To determine the long-term effects of intensive blood pressure (BP) lowering by antihypertensive drug therapy on aortic stiffness assessed by PWV, a single-blind randomized prospective study was performed., Methods: One hundred forty nondiabetic hypertensive patients (67.6 +/- 0.9 years old; systolic/diastolic BP: 177 +/- 1/101 +/- 1 mm Hg) were assigned to an intensive control group (IC) with a target BP of <130/85 mm Hg (n = 71) or a moderate control group (MC) with a target BP of <140/90 mm Hg (n = 69), and aortic stiffness was assessed every 3 months by measuring aortic PWV with a pulse pressure analyzer., Results: During the 12-month treatment period, BP significantly decreased to 129 +/- 1/78 +/- 1 mm Hg and 152 +/- 2/87 +/- 1 mm Hg in the IC and MC, respectively. At the beginning of the study, PWV in the IC and MC was similar, averaging 1779 +/- 41 and 1885 +/- 50 cm/sec, respectively. By the end of the treatment period, however, PWV had decreased to 1621 +/- 34 cm/sec in the IC, but had not changed significantly in the MC. In the IC, the ratio of the change in PWV to the change in BP increased with the duration of BP lowering. Clinical and biological parameters were similar in both groups, except that higher doses of amlodipine were used in the IC., Conclusions: Long-term intensive BP lowering in the hypertensive patients was associated with a significant reduction in aortic stiffness distinct from its acute depressor effect.

It has been reported that treatment with an angiotensin-converting enzyme (ACE) inhibitor is not adequate to suppress aldosterone, and we previously demonstrated that adding spironolactone to an ACE inhibitor may have beneficial effects on left ventricular hypertrophy (LVH) in selected patients with essential hypertension (EH). We have extended our previous short-term study, and addressed the relative long-term clinical effects of spironolactone and an ACE inhibitor in patients with EH who have LVH. Twenty patients with EH and concomitant LVH participated in this study. Subjects were treated with either an ACE inhibitor alone (group 1: 10 patients) or an ACE inhibitor plus spironolactone at the dose of 25 mg (group 2: 10 patients) for 60 weeks. The baseline clinical and echocardiographic characteristics of the two groups were similar. Final values of blood pressure were also similar between the two groups. The LV mass index (LVMI) decreased significantly in both groups, but the extent of reduction was significantly greater in group 2 at 60 weeks. The early peak to atrial peak filling velosities ratio (E/A ratio) was significantly increased to a similar extent in both groups. Serum procollagen type III amino-terminal peptide (PIIINP) was significantly decreased in group 2, but not in group 1. In group 2, there was a statistically significant correlation between the changes in LVMI and PIIINP. In conclusion, adding spironolactone to therapy with an ACE inhibitor for 60 weeks may have beneficial effects in patients with EH and concomitant LVH. Our study strongly suggests the possibility that attenuation of the effects of cardiac aldosterone in patients with EH by treatment with spironolactone and an ACE inhibitor may become a new goal for the prevention and regression of cardiac hypertrophy.

Background: Patients with a reduced nonlinear component of heart rate regulation have a poorer outcome., Methods and Results: We investigated whether a nonlinear correlation between renal sympathetic nerve activity (RSNA) and blood pressure or renal blood flow is reduced in conscious, spontaneously hypertensive rats (SHR) by comparing them with normotensive Wistar-Kyoto rats (WKY). We also determined the linearity and nonlinearity of the correlation in SHR who were given an angiotensin II receptor blocker, candesartan, orally for 2 weeks. The RSNA value was higher in SHR than in WKY, and coherence peaks of transfer function were found at 0.05 and 0.80 Hz (ie, below respiratory- and cardiac-related fluctuations). The coherence (linearity) of the transfer function was significantly higher and gain was smaller in SHR than in WKY. Because mutual information values (linear and nonlinear correlation) were similar in both strains, we found the nonlinear correlation to be lower in SHR than in WKY. Time delay values calculated by the mutual information method demonstrated that RSNA preceded blood pressure and renal blood flow by 0.5 to 1.0 s. In SHR given candesartan, the RSNA value was lower, and the linearity was lower and nonlinearity higher than SHR given vehicle., Conclusions: Linear correlation between RSNA and blood pressure or renal blood flow was higher in SHR than in WKY, whereas the nonlinear correlation was lower. Oral treatment with candesartan increased the nonlinearity and reduced the linearity in SHR. Increased RSNA and the renin-angiotensin system may be responsible for the lower nonlinearity and higher linearity in hypertension.

Objective: Increased Na+-H+ exchanger activity (NHE) has been reported as an intermediate phenotype in hypertensive subjects, particularly those with insulin resistance. To investigate whether NHE abnormality plays a role in hypertension, Wistar fatty rat (WFR) with overt obesity, hyperglycemia and marked hyperinsulinemia was examined., Methods: WFR and Wistar lean rats (WLR) as a control (n = 12, each) were fed either with normal (0.38%) or high sodium (4% NaCl) diet for 12 weeks and then sacrificed to examine platelets NHE activity., Results: Mean arterial pressure (MAP) was higher in WFR than in WLR (113 +/- 4 versus 96 +/- 7 mmHg, P < 0.05) under a normal chow. Vmax values of NHE activity were significantly higher in WFR than in WLR. WFR fed with a high sodium diet showed higher MAP than those with a normal chow (128 +/- 3 versus 113 +/- 4 mmHg, P < 0.05). Though Km values were not different between WFR and WLR under a normal chow, both maximal transport rate (Vmax) and half maximal transport (Km) values were significantly higher in WFR with a high salt diet than those with a control diet. Vmax showed significant correlation with MAP, whereas Km values correlated with immunoreactive insulin (IRI) levels. Significant interaction between dietary sodium intake and the strain differences was observed both on blood pressure and on IRI levels by two-way analysis of variance (ANOVA)., Conclusion: WFR presented salt-sensitive blood pressure elevation. NHE activity was enhanced in WFR in correlation with the blood pressure. These results suggest that augmented NHE activity contributes to the development of salt-sensitive blood pressure elevation in WFR.

We and others have reported that serum leptin levels are positively correlated with body mass index (BMI), blood pressure and heart rate (HR) in cross-sectional clinical studies. However, only a few longitudinal studies have focused on the relationships between leptin, BMI and blood pressure. The present study was performed to elucidate the relationships between baseline serum leptin levels and 2-year changes in BMI, blood pressure, HR and metabolic parameters in 314 Japanese male adolescents aged 16-17 years and in 225 Japanese men aged 30-63 years. Height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, fasting plasma glucose (FPG), serum lipids [total cholesterol (TC), triacylglycerols (TG), high-density-lipoprotein cholesterol (HDL-C) and low-density-lipoprotein cholesterol (LDL-C)], uric acid (UA), insulin and leptin levels were measured in the morning after an overnight fast. In the male adolescents, serum leptin levels in 1996 (log[leptin'96]) were significantly correlated with BMI, SBP, mean blood pressure and HR in 1998 (r=0.40, 0.13, 0.11 and 0.14, respectively). The percentage change in BMI per year (DeltaBMI) was negatively correlated with log[leptin'96], even after adjustment for baseline BMI (r=-0.12, P=0.030). In men aged 30-63 years, log[leptin'96] was also positively correlated with BMI'98, SBP'98, DBP'98, FPG'98, TC'98, log[TG'98], LDL-C'98 and UA'98 (all P<0.05), and negatively correlated with HDL-C'98, DeltaBMI, DeltaFPG, DeltaTC and DeltaLDL-C. The relationship between log[leptin'96] and DeltaTC was significant, even after adjustment for initial BMI (r=-0.15, P=0.023). These findings therefore suggest that serum leptin levels are correlated with subsequent decreases in BMI and TC in Japanese men.

Objective: This study was aimed to evaluate the determinants of elevated blood pressure (BP) in adolescents., Design and Methods: We retrospectively evaluated the BP and anthropometric data in 419 Japanese students (268 males and 151 females) during high school and university. Their annual health records were analysed for BP, heart rate, height and body weight between the ages of 15 and 21 years., Results: The number of hypertensive students did not vary significantly during the 6 years. Concerning changes in BP categories according to the modified JNCVI classification between the ages of 15 to 21 years, 150 males kept a normal BP (keeping normal BP group); 39 males developed high BP (developing high BP group); 37 males kept high BP (keeping high BP group); and 42 males became normal BP (becoming normal BP group). The majority of females (n = 144, 95.4%) were included in the keeping normal BP group. In male students, both the keeping and becoming normal BP groups, especially the latter, showed a significant decrease in heart rate over the 6 years, while the other two groups showed no change. The height and body weight of each of the four groups showed a significant increase, but the body mass index (BMI) of the males in the becoming normal BP group did not increase over the 6 years. Body weight and BMI at the age of 15 years in the male keeping normal BP group were significantly below that of the other three groups; this difference persisted at the age of 21 years. Furthermore, male university students who showed a BP above 'high-normal' at the age of 21 years exhibited a significantly higher BP, heart rate, body weight and BMI than did the normotensives, when they were high school students. Stepwise regression analysis of the data showed that the best predictors of BP at the age of 21 years were the initial high school BP and BMI levels and changes in BMI and heart rate during the 6-year period for male students., Conclusion: Results indicate that the BP and BMI during high school and the changes in BMI and heart rate from high school to university influenced the BP at the age of 21 years in male students. Data indicate that information on the prevention and management of hypertension including weight control should begin early, especially in male adolescents.

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.

Numerous epidemiological studies have shown a close relationship between obesity and hypertension. However, there have been few reports on the relationship between changes in the body weight and blood pressure of lean to normal-weight young subjects. The purpose of this study was to investigate the effects of body weight control on blood pressure in lean to obese young Japanese individuals in a 3-year follow-up study. University students (3,558 males and 1,418 females, aged 18.6+/-0.8 in 1994) were classified into 4 groups according to the baseline body mass index (BMI), and were followed up for 3 years. Among male students, changes in body weight were significantly correlated with changes in blood pressure during the 3 years in all 4 BMI groups, and the correlation coefficient was larger in the group with higher baseline BMI. Positive correlations between changes in body weight and changes in heart rate were noted only in the obese and mildly-obese groups. Also in female students, positive correlations were observed between changes in body weight and changes in blood pressure in lean to obese groups. However, no correlations between changes in body weight and changes in heart rate were noted in any of the female groups. To summarize, close correlations were observed between changes in body weight and those in blood pressure during the 3 years in both male and female university students. These findings suggest the importance of body weight control not only in obese but also in normal to mildly-obese young subjects in reducing or preventing an increase in blood pressure. There could be, however, a gender difference in the effects of body weight change on heart rate.

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.

The effects of belonging to sports clubs on male high school students was evaluated. The relationships between the type and extent of school-based exercise were examined in conjunction with percent body fat, blood pressure (BP), and other key metabolic parameters. A total of 264 male Japanese high school students (age range: 17-18 years old) were studied. Percent body fat was measured and blood was collected in the fasting state during a routine health check. Subjects were divided into two groups. The exercise (E) group (n=150) included students who had belonged to a sports club during the past 2 years. The non-exercise (NE) group (n=114) included students who did not belong to a sports club during the past 2 years. The body mass index was significantly greater in group E (21.7 +/- 2.3 (SD) kg/m2) than in group NE (20.7 +/- 2.6 kg/m2, p < 0.01). However, the percent body fat in group E (13.6 +/- 3.4%) was significantly lower than that in group NE (14.9 +/- 3.8%, p < 0.01). The diastolic BP and heart rate in group E (64 +/- 7 mmHg, 70 +/- 11/min) were significantly lower in group E than in group NE (66 +/- 8 mmHg, p < 0.05; 76 +/- 14/min, p < 0.01). The serum triglyceride level was significantly lower, and the HDL cholesterol level was higher in group E than in group NE. The homeostasis model assessment (HOMA) index, used as an index of insulin resistance, was similar in the two groups. However, the level of the HOMA index was significantly lower among the 62 subjects in group E who preferred highly dynamic exercise (1.50 +/- 0.46) than it was among those in group NE (1.66 +/- 0.49, p < 0.05). Results indicate that belonging to sports clubs influences the BP and lipid profiles of adolescent males, as well as their percent body fat. In view of the reduction of cardiovascular risk factors, it is recommended that even young males practice regular exercise, especially aerobic exercise.

This study was designed to examine the relationships between birth weight or current body weight and blood pressure (BP) or cholesterol in 178 Japanese high school students (98 male, 80 female, age 15-16 yr). All subjects were born after a full-term pregnancy (gestational age > or = 38 wk) with a birth weight > or = 2,500 g; these data were obtained from routine obstetrical records. At a health check-up, nurses used an automatic device to perform two consecutive BP measurements with each subject in a sitting position after resting for at least 5 min. Serum total and high-density lipoprotein (HDL) cholesterol levels were measured. Birth weight was not related to BP, but was inversely related to serum total cholesterol in both males (r= -0.241, p < 0.05) and females (r= -0.351, p < 0.01). Current body weight was significantly related to systolic BP (r=0.369, p<0.01), diastolic BP (r=0.216, p<0.05), and HDL cholesterol level (r= -0.224, p < 0.05) in males, but not in females. Although no relationship was demonstrated between birth weight and BP level in young Japanese students without intrauterine growth retardation, an inverse relationship between birth weight and serum total cholesterol level was found. There was a gender difference in the relationship between current body weight and either BP or HDL cholesterol in these subjects.

It has not been examined whether the pressure-natriuresis response is altered in the insulin-resistant condition. Furthermore, despite an important role of nitric oxide (NO) in modulating pressure-natriuresis, no investigations have been conducted assessing the renal interstitial NO production in insulin resistance. The present study examined whether pressure-natriuresis was altered in insulin-resistant obese Zucker rats (OZ) and assessed the cortical and medullary nitrate/nitrite (NOx) levels with the use of the renal microdialysis technique. In OZ, serum insulin/glucose ratio (23.0+/-4.0x10(-8), n=9) and blood pressure (119+/-3 mm Hg) were greater than those in lean Zucker rats (LZ; 7.0+/-1.9x10(-8) and 103+/-4 mm Hg, n=9). The pressure-natriuresis curve in OZ was shifted to higher renal perfusion pressure (RPP), and the slope was blunted compared with that in LZ (0.073+/-0.015 vs 0.217+/-0.047 microEq/min kidney weight/mm Hg, P<0.05). The basal renal NOx level was reduced in OZ (cortex, 4.032+/-0.331 micromol/L; medulla, 4. 329+/-0.515 micromol/L) compared with that in LZ (cortex, 7.315+/-1. 102 micromol/L; medulla: 7.698+/-0.964 micromol/L). Furthermore, elevating RPP increased the medullary NOx in LZ, but this pressure-induced response was lost in OZ. Four-week treatment with troglitazone, an insulin-sensitizing agent, improved hyperinsulinemia, systemic hypertension, and basal renal NOx levels (cortex, 5.639+/-0.286 micromol/L; medulla, 5.978+/-0.284 micromol/L), and partially ameliorated the pressure-natriuresis curves; the slope of pressure-natriuresis curves and elevated RPP-induced NOx, however, were not corrected. In conclusion, our study suggests that insulin resistance is closely associated with abnormal pressure-natriuresis and hypertension. These deranged renal responses to insulin resistance are most likely attributed to impaired medullary NO production within the medulla.

Many studies have suggested an association between blood pressure (BP) and both insulinaemia and haematocrit values in Western populations. However, relatively few data regarding such associations for the Japanese population are available. We investigated the relationship between BP and various parameters, including insulin and haematocrit, in 269 healthy Japanese individuals (113 men and 156 women) over 60 years of age. The data were analysed by stepwise multiple regression analysis. In men, the most important determinant of systolic BP (SBP) and diastolic BP (DBP) was the plasma insulin concentration (beta = 0.32, F = 12.4, P < 0.001 and beta = 0.32, F = 13, P < 0.001, respectively), and haematocrit was found to be associated with DBP (beta = 0.21, F = 5.3, P < 0.05). In women, fasting insulins were unrelated to BP, but fasting plasma glucose and triglyceride concentrations and age were associated with SBP (beta = 0.29, F = 15.5, P < 0.001, beta = 0.27, F = 14.3, P < 0.001, and beta = 0.2, F = 7.8, P < 0.01, respectively), and haematocrit, fasting plasma glucose concentration and age were associated with DBP (beta = 0.29, F = 14, P < 0.001, beta = 0.2, F = 6.9, P < 0.01 and beta = 0.2, F = 6.3, P < 0.05, respectively). These results suggest that the insulin-BP associations in healthy Japanese subjects over 60 years of age differ according to sex, and that haematocrit is an important determinant of DBP in both sexes in our population.

Our objective was to determine whether increased salt sensitivity after menopause precedes the development of overt hypertension. We investigated the effect of ovariectomy on pressure natriuresis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats by in vivo perfusion studies. Differences in the neural and hormonal backgrounds of the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The pressure-natriuresis relationship was blunted in DS rats compared with DR rats (slope, 0.30 versus 0.63 mumol.min-1.g kidney wt-1.mm Hg-1, P < .01). The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy (from 0.30 to 0.14 mumol.min-1.g kidney wt-1.mm Hg-1, P < .05), and that of DR rats was not. The ovariectomized DS rats developed hypertension earlier than sham-operated DS rats by salt loading. These results show that ovariectomy enhances genetic salt sensitivity by blunting the pressure-natriuresis relationship, which precedes the development of overt hypertension in female DS rats.

1. We investigated the effects of antihypertensive treatment (8 weeks) with four different agents (trichlormethiazide, atenolol, nicardipine and enalapril) on baroreceptor function in 28 week old spontaneously hypertensive rats (SHR) to measure aortic depressor nerve (ADN) activity. 2. Threshold pressure (Pth) of ADN activity was elevated and the gain sensitivity of the pressure-activity curve, as determined by the maximum gain (Gmax) of a logistic function curve, was depressed in untreated SHR compared to those in untreated Wistar-Kyoto (WKY) rats. 3. Treatment with the four agents similarly reduced blood pressure in SHR. Each of the four agents induced a decrease in Pth and an increase in Gmax to a similar extent in SHR. 4. These findings suggest that antihypertensive therapy in chronic hypertension augments baroreceptor function through the lowering of blood pressure but not through specific pharmacological actions.

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.

The preoptic region of hypothalamus was disconnected from caudal structures with two different-size knife cuts in rats to investigate the pathway responsible for the effects of intracerebroventricular (ICV) and intravenous (IV) angiotensin II (ang II) on blood pressure and arginine vasopressin (AVP) release. Seven days after surgery ICV ang II (125 ng) in sham-operated (sham) rats increased mean arterial pressure (MAP) (+23 +/- 3 mmHg) and decreased heart rate (HR) (-58 +/- 5 beats/minute). However, ICV ang II had no effect on MAP or HR of rats with a large (preoptic-hypothalamic disconnection) cut. Both the pressor response (+12 +/- 2 mmHg) and the bradycardia (-39 +/- 6 beats/minute) were significantly reduced by a small (medial preoptic-hypothalamic disconnection) cut. The increased plasma AVP to ICV ang II in sham rats (9.8 +/- 3.6 pg/mL) was abolished in large-cut rats and attenuated in small-cut rats (3.2 +/- 0.7 pg/mL). IV bolus injection of ang II (125 ng) in sham rats increased MAP by 43 mmHg, whereas large-cut rats showed a blunted (25%) pressor response. The pressor response to IV infusion of ang II (8 ng/20 microL/minute for 15 minutes) was diminished in large-cut rats (+4 +/- 1 mmHg) as compared with that in sham rats (+19 +/- 2 mmHg). Both cuts transected the projection between the periventricular tissue surrounding the anteroventral third ventricle and supraoptic nucleus, but the supraoptic-neurohypophyseal pathway was severed only by the large cut.(ABSTRACT TRUNCATED AT 250 WORDS)

To explore the syndrome of glucocorticoid-induced hypertension in the elderly, we analyzed the clinical findings from 35 patients aged more than 65 years (12 men, 23 women) who received glucocorticoid therapy. Resting blood pressures (BP) were less than 140/90 mm Hg before glucocorticoid therapy, and patients were apparently disease-free apart from the condition for which glucocorticoid therapy was prescribed. Glucocorticoid-induced hypertension is defined as systolic BP more than 160 mm Hg and/or diastolic BP more than 95 mm Hg after glucocorticoid administration. Glucocorticoid-induced hypertension was seen in 13 patients (37.1%); all patients with hypertension [steroid (glucocorticoid)-induced hypertension (SH(+)) group] received more than 20 mg of prednisolone daily, and BP rose rapidly within a week of commencing glucocorticoid administration. The SH(+) group did not differ significantly in terms of age, heart rate, blood count, plasma biochemistry, plasma renin activity, plasma aldosterone, routine urinalysis, or urinary electrolytes from patients who did not show hypertension [SH(-) group]. However, serum total calcium concentrations were significantly lower in the SH(+) group both before and after 2 weeks of glucocorticoid therapy than in the SH(-) group. Furthermore, the SH(+) group showed a significantly higher percentage of patients with a positive family history of essential hypertension than the SH(-) group. In conclusion, although the detailed mechanisms are as yet uncertain, glucocorticoid-induced hypertension occurs often in elderly patients, and is more common in patients with total serum calcium concentrations lower than the normal range, and/or in those with positive family history of essential hypertension.

Efficacy of orally available, selective vasopressin V1 and V2 receptor antagonists on the developing and established stage of DOCA-salt hypertension was investigated. Twenty-nine Wistar rats were heminephrectomized, and administered DOCA (50 mg/kg; intraperitoneally twice a week) and salt (5% NaCl diet) from week 0 to the end of study. Group 1 rats were served as control. Group 2 and 5 rats were given a V1 antagonist, and groups 3 and 6 rats were given a V2 antagonist, while groups 4 and 7 rats received both V1 and V2 antagonists. Each drug was started to groups 2, 3 and 4 at week 0, and to groups 5, 6 and 7 at week 4. Significant amelioration of the increase in blood pressure was observed in groups 3 and 4 at week 10, and a reduction in blood pressure occurred in groups 6 and 7 at week 10. Otherwise, a V1 antagonist alone slightly attenuated blood pressure rise in the group 2 without significance, and failed to lower blood pressure of the group 5 during the study. These results suggest that both V1 and V2 agonisms are involved in an increase in blood pressure at the developing stage of DOCA-salt hypertension, and that V2 agonism, but not V1 plays a major role in the maintenance of high blood pressure at the established stage.

The clinical efficacy and safety of bevantolol hydrochloride, a newly developed beta-blocker, used in combination with other types of antihypertensive agents, were evaluated in patients with severe hypertension by multicenter open-label trials. A total of 28 patients were studied at 20 medical centers. Four patients (14.3%) were excluded for some reasons, and the remaining 24 patients (22 outpatients and 2 inpatients) were analyzed. Following the initiation of therapy, blood pressure decreased from 181 +/- 15 (SD)/114 +/- 3 mmHg to 170 +/- 17/102 +/- 8 mmHg (p < 0.01) on the 14th day of the therapy and gradually lowered further thereafter. At the end of the trial (8th week), blood pressure was stabilized at the level of 160 +/- 14/96 +/- 10 mmHg. The antihypertensive efficacy rated by the changes in mean blood pressure was 79.2% (19/24). Pulse rate decreased slightly but significantly from 75 +/- 10 beats/min to 70 +/- 7 (p < 0.05) on the 14th day of the therapy and stabilized at the similar level thereafter. As abnormal laboratory data were detected in 3 patients and 1 patient complained of a mild headache, the safety ratio was 83.3% (20/24 patients). When the usefulness was assessed in terms of antihypertensive efficacy and safety profiles, bevantolol hydrochloride was considered useful in 75.0% of the patients studied. In conclusion, bevantolol hydrochloride, used in combination with other classes of antihypertensive agents, appears to be an excellent drug for the management of patients with severe hypertension.

To determine whether any differences exist between young male subjects with elevated diastolic and systolic blood pressure (BP) and those with only an elevated systolic BP, the responses of BP and plasma catecholamines to a mental arithmetic test were studied in 11 young men (mean age of nineteen years) with BP of > or = 140/90 mm Hg at a routine health check-up (group I-hypertension [HT]), 26 age-matched men with only elevated systolic BP (> or = 140 mm Hg) (group II-HT), and 12 age-matched normotensive (NT) men (< 140/90 mm Hg). During an arithmetic test, group I-HT showed a significantly higher increment of systolic BP (+14.5-18.0%) than group II-HT (+9.3-10.2%) and NT controls (+6.4-8.2%). However, no significant difference in BP response was seen between group II-HT and NT controls. Plasma norepinephrine in group I-HT showed a significant increase after the test, (171 +/- 23-->202 +/- 27 pg/mL), whereas group II-HT and NT controls showed no change. No significant difference occurred in epinephrine response among the three groups. These results suggest that the young male subjects with screening BP above 140/90 mm Hg are hyperreactive to a mental stress as compared with subjects with only elevated systolic BP or NT controls.

We investigated the relation between home blood pressure (BP) and body weight in 38 young normotensive men (mean age, 16 years) whose parents were normotensive (PNT group) and 34 age- and sex-matched normotensive men, one or both of whose parents were hypertensive (PHT group). Although causal BP measurements were similar in both groups, home systolic BP was significantly higher in the PHT group (123 +/- 1 mm Hg) than in the PNT group (116 +/- 1 mm Hg). Body weight was significantly greater in the PHT group (66.0 +/- 1.4 v 61.8 +/- 1.3 kg, P < .05) and body mass index (BMI) was not significantly higher in the PHT group (22.4 +/- 0.5 v 21.3 +/- 0.5 kg/m2, P = .09). Body weight (r = 0.38) and BMI (r = 0.42) were significantly correlated with home systolic BP in the PHT group. There were no differences in serum lipid or uric acid concentrations between the two groups. Our results showed that young normotensive subjects with a genetic predisposition to hypertension weighed more and had higher home systolic BPs compared with subjects without a family history of hypertension. Our observations further indicated a close relationship between a family history of hypertension and increased body weight, even in young normotensive men.

The effects of a calcium channel blocker, nicardipine, on pressure-natriuresis responses were studied in Dahl salt sensitive (DS) and resistant (DR) rats. Differences in the neural and endocrine background were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The renal plasma flow (RPF) and glomerular filtration rate (GFR) of DS rats were disautoregulated in the low renal perfusion pressure range, while those of DR rats were autoregulated. Administration of nicardipine (0.3 microgram/kg/min) into the renal artery significantly increased RPF and GFR and abolished the autoregulation in both strains of rats. Nicardipine also sharpened the pressure-natriuresis responses in both strains without changes in fractional excretion of sodium. These findings suggest that nicardipine increased GFR and thereby improved the pressure-natriuresis responses of DS rats.

This study was designed to elucidate how central and peripheral arginine vasopressin (AVP) interacts with the sympathetic nervous system and the renin-angiotensin system to maintain blood pressure in two-kidney, one-clip hypertensive rabbits. We recorded renal sympathetic nerve activity (RSNA) in the conscious state as an index of sympathetic nervous system function. The changes in mean arterial pressure, heart rate, and RSNA were recorded continuously for 60 minutes after intravenous administrations of captopril (2.5 mg/kg) and nicardipine (3.2 micrograms.kg-1.min-1) in eight identical rabbits. Despite equivalent reductions in mean arterial pressure (10 +/- 1 mm Hg), the increase in RSNA was significantly larger with captopril than that with nicardipine, and the plasma concentration of AVP was elevated (from 100% to 255 +/- 24%) with captopril. Mean arterial pressure was reduced, and RSNA was increased by intravenous infusion of AVP antagonist d(CH2)5Tyr(Me)AVP (n = 8), whereas vertebral artery infusion of the antagonist (n = 6) did not change RSNA. During central and peripheral infusions of AVP antagonist, RSNA was exaggerated by blood pressure reduction with nicardipine as well as with captopril. Increases in RSNA induced by captopril and nicardipine were larger by central infusion of AVP antagonist than by intravenous infusion. The decrease in mean arterial pressure by captopril (30 +/- 4 mm Hg) in eight sinoaortic-denervated hypertensive rabbits was larger than that in hypertensive rabbits with intact baroreflex. These data suggest that compensatory activation of RSNA was revealed by central and peripheral attenuation of AVP and that the sympathetic nervous system became the most important mechanism for blood pressure maintenance in the absence of AVP. The interaction of AVP with the sympathetic nervous system may be independent of the state of the renin-angiotensin system, since the exaggeration of RSNA by AVP antagonist was qualitatively the same with nicardipine as with captopril. In conscious renal-hypertensive rabbits, AVP in the central nervous system played a substantial role when blood pressure was reduced, although it did not contribute to blood pressure maintenance in the basal condition.

The effects of sodium (Na+) and chloride ions (Cl-) on blood pressure were studied in rats treated with deoxycorticosterone acetate (DOCA). Four groups were prepared, each consisting of male Wistar rats that underwent heminephrectomy and administration of DOCA: the control group was maintained with tap water, the NaCl group with tap water containing 1% sodium chloride, the NaCit group with tap water containing 1.67% sodium citrate (including an equivalent dose of Na+ to 1% NaCl), and the ChoCl group with tap water containing 1.15% choline chloride (including an equivalent dose of Cl- to 1% NaCl). The time-course of systolic blood pressure showed only slight change in blood pressure in the control and ChoCl groups, and in the NaCl and NaCit groups. The rotational correlation time, an index of the fluidity of erythrocyte membrane, with spin-labeling of 16-doxyl-stearic acid, was significantly (p < 0.05) higher in the NaCl and NaCit groups than in the control group, indicating an increase in the membrane fluidity, i.e., membrane fragility. The sodium, potassium ions-activated adenosine triphosphatase (Na+,K(+)-ATPase) activity of the erythrocyte membrane was decreased to 22% (P < 0.01) and 24% (P < 0.01) in the NaCl and NaCit groups, respectively, compared with the control groups; this activity was decreased to 43% in the ChoCl group (P < 0.05). The Ca(2+)-ATPase activity showed similar changes. In contrast, there were no marked differences in the erythrocyte electrolyte level between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the role of the endothelium-derived relaxing factor nitric oxide (NO) on pressure-natriuresis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using in vivo perfusion studies. Differences in the neural and hormonal background to the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. In WKY, elevation of renal perfusion pressure (RPP) from 115 to 157 mm Hg increased urinary sodium excretion 4.5 to 14.8 microEq/min/g kidney wt, and the slope of its linear regression was 0.21 microEq/min/g kidney wt/mm Hg. Infusion of an inhibitor of NO synthase, L-NMMA (1 mg/min/kg), lowered this slope (P < 0.05) but L-arginine (3 mg/min/kg) did not change it. By contrast, the impaired pressure-natriuresis response of SHR was ameliorated by L-arginine (slope: 0.08 to 0.16; P < 0.05), while L-NMMA did not blunt it further. GFR and renal plasma flow (RPF) were well autoregulated in both strains, but L-NMMA lowered RPF significantly (SHR: from 4.2 to 2.6 ml/min/g kidney wt; WKY: 4.5 to 2.5 ml/min/g kidney wt). Moreover, when infused simultaneously, all these individual effects of L-NMMA and L-arginine were nullified. These results suggest that NO plays an important role in the pressure-natriuresis mechanism.

Accumulating evidence, including a wide distribution of specific receptors for aldosterone in the brain, has revealed a potential role of aldosterone in the central nervous system. However, whether or not aldosterone is present in cerebrospinal fluid remains unclear. We attempted to detect aldosterone in cerebrospinal fluid in 14 normotensive subjects. Cerebrospinal fluid was obtained by lumbar puncture. Aldosterone-like immunoreactivity was detected in cerebrospinal fluid (163 +/- 5 pmol/l, range 139-211 pmol/l) and was found to significantly correlate to both plasma aldosterone (r = 0.70, p less than 0.01) and plasma renin activity (r = 0.68, p less than 0.01). However, no significant relationship was found between aldosterone-like immunoreactivity in cerebrospinal fluid and the level of sodium or potassium in cerebrospinal fluid or mean blood pressure. Although we confirmed the presence of aldosterone-like immunoreactivity in cerebrospinal fluid of normotensive subjects, the physiological role of aldosterone in cerebrospinal fluid has yet to be elucidated. Further study will thus be needed to determine the role of cerebrospinal fluid aldosterone.

Objective: The aim of this study was to investigate the role of depressor systems in glucocorticoid-induced hypertension., Methods: The serial changes in cardiorenal hemodynamics, urinary excretions of kallikrein and prostaglandins (PGE2 and the prostacyclin derivative 6-keto-PGF1 alpha) before, and during the administration of both low and high doses of dexamethasone (9 alpha-fluoro-16 alpha-methylprednisolone) and after the cessation of dexamethasone were examined in conscious trained dogs. In addition, pressor responses to prostaglandin, bradykinin, bradykinin antagonist and indomethacin were studied during the administration of dexamethasone., Results: High-dose dexamethasone induced a significant elevation in mean arterial pressure (MAP) that was accompanied by a significant reduction in the urinary excretion of kallikrein, PGE2 and 6-keto-PGF1 alpha. In contrast, low-dose dexamethasone treatment had no significant effect upon MAP but induced a transient elevation in the urinary excretion of kallikrein, PGE2 and 6-keto-PGF1 alpha. Furthermore, additional oral administration of indomethacin produced a significant elevation in MAP in dogs treated with low-dose dexamethasone; but did not affect the hemodynamics of animals with high-dose dexamethasone. Whilst i.v. administration of either bradykinin or prostacyclin induced a significant reduction in MAP in high-dose but not low-dose dexamethasone-treated dogs, administration of a competitive bradykinin antagonist, D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin induced a significant elevation in MAP in low-dose but not high-dose dexamethasone-treated dogs., Conclusion: Depressor systems play an important role in regulation of blood pressure in glucocorticoid-treated dogs.

1. Under hormonally constant conditions, the effects of a sudden increase in blood pressure on the release of endothelium-derived relaxing factor were evaluated by measuring urinary excretion of NO2-/NO3- in rats with renal denervation. 2. Elevation of blood pressure from 136 +/- 2 to 153 +/- 3 mmHg by an aortic clamp below the renal arteries induced a significant increase in urinary excretion of NO2-/NO3- from 76.6 +/- 4.2 x 10(2) to 108.1 +/- 8.3 x 10(2) pmol min-1 g-1 kidney weight (P less than 0.05). 3. Infusion of NG-monomethyl-L-arginine (1 mg min-1 kg-1) without an aortic clamp raised mean blood pressure to a similar level; however, urinary excretion of NO2-/NO3- was decreased significantly. 4. During infusion of NG-monomethyl-L-arginine, aortic occlusion caused a significant increase in blood pressure without any changes in NO2-/NO3- excretion in the urine. 5. These results suggest that the formation of NO, an indicator of endothelium-derived relaxing factor release, was increased by mechanical pressure elevation without apparent changes in hormonal and neural factors.

L-Arginine, the precursor of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO), was administered intravenously in five patients with essential hypertension, one with renovascular hypertension, one with primary aldosteronism, and one with Cushing's syndrome. During the administration, the mean arterial pressure decreased concomitantly with an elevation of cardiac output and a fall in total peripheral resistance in all cases. Indicators of NO release in vivo such as plasma concentrations of L-citrulline and urinary excretion of nitrite/nitrate increased simultaneously during the administration. These results suggest that exogenous L-arginine can produce a vasodilatory effect via stimulating NO release in hypertensives.

The purpose of this study was to investigate the effects of 4-week oral administration of manidipine (40 mg daily), a newly developed calcium channel blocker, on blood pressure and renal function in salt-loaded (8% NaCl) spontaneously hypertensive rats. Systolic blood pressure of spontaneously hypertensive rats increased from 167 +/- 4 to 221 +/- 7 mmHg with salt loading for 4 weeks; manidipine completely prevented this elevation in blood pressure. Urinary excretion of sodium in salt-loaded spontaneously hypertensive rats was twelve-fold compared with those receiving a normal diet (0.38% NaCl). The pressure-natriuresis relationship was obtained during week 4 of the metabolic study. At similar renal perfusion pressures, sodium excretion was significantly higher in salt-loaded rats than in rats fed a normal diet. Glomerular filtration rate and renal plasma flow were similar between the two groups. In salt-loaded spontaneously hypertensive rats, treatment with manidipine improved the pressure-natriuresis relationship toward lower pressures. Further, manidipine attenuated the autoregulation of glomerular filtration rate and renal plasma flow. These results indicate that manidipine normalizes the relation between sodium excretion and renal perfusion pressure in salt-loaded spontaneously hypertensive rats by resetting pressure natriuresis.

We measured blood pressure, platelet cytosolic calcium concentration ([Ca2+]i) and vasoactive hormones in 20 anuric normotensive patients on chronic hemodialysis (HD) to clarify the role of cytosolic calcium in regulation of blood pressure. All measurements were performed at the end of HD (post-HD) and at the beginning of the next HD (pre-HD). During the HD-HD interval, mean blood pressure increased from 85 +/- 4 to 94 +/- 4 mm Hg (mean +/- SEM, p less than 0.05), but the median [Ca2+]i in platelets did not show any significant change (133 +/- 5 vs. 136 +/- 5 nmol/l). Although all patients were within their ideal body weight at post-HD, platelet [Ca2+]i did not correlate with mean blood pressure. By contrast, platelet [Ca2+]i correlated with mean blood pressure (r = 0.489, p less than 0.05) at pre-HD. Moreover, platelet [Ca2+]i at post-HD also correlated with changes in mean blood pressure during the HD-HD interval (r = 0.532, p less than 0.05). In addition, there were negative correlations between platelet [Ca2+]i and plasma renin activity both post- and pre-HD (r = -0.652, p less than 0.005; r = -0.673, p less than 0.005; respectively). These results suggest that cytosolic calcium plays important roles in regulation of renin secretion and in the elevation of blood pressure induced by volume expansion in patients on chronic HD.

To examine the role of prostaglandins on pressure natriuresis in Dahl salt-sensitive (DS) rat, the pressure-natriuresis relationships in DS and Dahl salt-resistant (DR) rats were characterized with or without indomethacin (2 mg/kg/h) by utilizing an in vivo renal perfusion study. When untreated, in the DS rat the pressure-natriuresis curve was blunted (P less than .05) and excretion of prostaglandin E2 (38 +/- 11 to 109 +/- 43 pg/min) was decreased in comparison to the DR rat. With indomethacin, the pressure-natriuresis curve in the DR rat was blunted, while no significant changes were observed in the DS rat. Plasma renin activity and concentration of atrial natriuretic peptide were not changed by the treatment of indomethacin in both strains. These results suggest that the decrease in renal prostaglandins, at least in prostaglandin E2, plays some role in blunting pressure natriuresis in DS rat.