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

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

We evaluated the relationship between admission blood pressure (BP) and early prognosis in patients with acute stroke in a single cohort.The subjects comprised 1004 cases of brain infarction and 1097 cases of brain hemorrhage, who were admitted to hospitals on the day of stroke onset. Death within 30 days after onset was evaluated in relation to admission BP levels.In brain infarction, a U-shaped relationship was found between BP levels and mortality rate, with a nadir at systolic blood pressure (SBP) of 150-169 mmHg and at diastolic blood pressure (DBP) of 100-110 mmHg. After adjustments for age and sex, the highest relative risks (RR) was observed in the lowest BP levels compared with nadir groups, and were 2.69 [95% confidence interval (CI), 1.43-5.07] in SBP and 3.49 (95% CI, 1.58-7.74) in DBP. In subjects with previous hypertension, the relationship between prognosis and SBP level shifted significantly toward higher pressure by about 10 mmHg compared with those without previous hypertension. In subjects with brain hemorrhage, the relationship between BP levels and mortality rate showed a J-shape in SBP and a U-shape in DBP. Highest BP levels had the poorest prognoses (/= 230 mmHg in SBP, RR = 4.13, 95% CI = 2.45-6.94;/= 120 mmHg in DBP, RR = 1.83, 95% CI = 1.11-3.04).Lower and higher BP after brain infarction and higher BP after brain hemorrhage were predictors for poor early prognosis. In subjects with brain infarction, patients with previous hypertension had better outcomes at higher admission BP level than did normotensive patients.

Blood pressure as a risk factor for development of end-stage renal disease has not been fully studied, particularly in women. We studied the development of end-stage renal disease from 1983 through 2000 in 98 759 subjects, 46 881 men and 51 878 women, 20 to 98 years of age, who were screened in 1983 in Okinawa, Japan. Data for all dialysis patients registered from 1983 to 2000 in Okinawa were used to identify the screened subjects in whom end-stage renal disease developed. In follow-up, 400 subjects, 231 men and 169 women, had end-stage renal disease. Age, body mass index, and adjusted relative risk for systolic and diastolic blood pressure for both men and women were measured. When these results were compared with an optimal blood pressure, the relative risk of development of end-stage renal disease for those with high-normal blood pressure and hypertension were significant in both men and women. Hypertension is a significant risk factor for development of end-stage renal disease not only in men but also in women. Control of blood pressure within normal levels should be stressed as a strategy to prevent end-stage renal disease in both men and women.

Calcitonin receptor–like receptor/receptor activity–modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.

OBJECTIVE To clarify the role of insulin resistance and hyperinsulinaemia in the pathogenesis of obesity-related hypertension. DESIGN An open study comparing the effects of weight reduction by low-energy diet and treatment with troglitazone, an insulin-sensitizing agent. SETTING A tertiary teaching hospital. PATIENTS Thirty overweight hypertensive patients (15 men and 15 women, mean age 61 years, mean body mass index 29.1 kg/m2). INTERVENTIONS Fifteen patients were assigned to a weight-reduction programme by low-energy diet (3360 kJ/day) for 3 weeks; the remaining 15 patients were treated with troglitazone (400 mg/day) for 8 weeks. MAIN OUTCOME MEASURES Casual and ambulatory blood pressures, glucose and lipid metabolism, and insulin sensitivity. RESULTS The baseline values of body mass index, fasting and post-glucose plasma insulin, and casual and ambulatory blood pressures were comparable between the two groups. Weight reduction (4.1 +/- 0.3 kg, mean +/- SEM) was associated with significant decreases in plasma insulin, blood glucose, homeostasis model assessment (HOMA) insulin resistance index, serum triglyceride, casual blood pressure (7.7 +/- 2.3/ 3.9 +/- 1.4 mmHg) and 24 h blood pressure (8.3 +/- 1.9/ 4.3 +/- 1.1 mmHg). Treatment with troglitazone caused comparable decreases in the metabolic parameters and HOMA index, but did not change casual or 24 h blood pressure (0.8 +/- 3.4/0.8 +/- 2.1 and 1.5 +/- 2.4/ 1.0 +/- 1.9 mmHg, respectively). CONCLUSIONS Insulin resistance/hyperinsulinaemia may not have an important role in the pathogenesis of obesity-related hypertension. The antihypertensive effect of weight reduction seems to be mediated mainly by other mechanisms.

Background Dihydropyridine calcium antagonists increase heart rate due to reflex activation of the sympathetic nervous system, although these effects are less obvious for long-acting agents. Objective To study the effects of diltiazem retard, a long-acting nondihydropyridine calcium antagonist, on 24h blood pressure, heart rate and autonomic nerve activity in patients with essential hypertension. Design Randomized crossover design. Methods Thirteen patients [five men and eight women, aged 64+/-2 years (mean+/-SEM)] were administered placebo or diltiazem retard (100-200mg once daily) for 4 weeks each. Ambulatory monitoring of blood pressure and heart rate, and electrocardiography were carried out at the end of each period using a multibiomedical recorder (TM-2425). Autonomic nerve activity was evaluated by power spectral analysis of variability of heart rate using the high-frequency component as an index of parasympathetic nerve activity and the ratio of the low-frequency component and the high-frequency component as an index of sympathovagal balance. Results Treatment with diltiazem retard significantly decreased 24h average blood pressure and heart rate by 11.6+/-3.6/5.7+/-1.8mmHg and 5.0+/-1.1 beats/min, respectively. The changes in daytime and night-time values were comparable. Diltiazem retard also significantly decreased daytime and 24h low:high-frequency-component ratio (2.0+/-0.2 versus 1.7+/-0.2 and 1. 8+/-0.2 versus 1.6+/-0.2, respectively). Conclusions These results indicate that diltiazem retard is effective as a once-daily antihypertensive agent and has favorable effects on heart rate and the autonomic nervous system.

Abstract It has been reported that plasma concentrations of adrenomedullin (AM), a novel vasodilator peptide, are higher in patients with essential hypertension than those in normotensive subjects. To clarify the clinical significance of increased levels of AM in patients with essential hypertension, in this study we examined the relationship between plasma concentrations of AM and the structure of the left ventricle or carotid artery. Plasma AM concentrations; renin activity; and norepinephrine, epinephrine, and creatinine concentrations in 50 patients with untreated essential hypertension without renal dysfunction and heart failure were measured. We also measured the mean wall thickness of the left ventricle and left ventricular mass index by M-mode echocardiography and intimal-medial thickness and arterial distensibility of the carotid artery by ultrasonography. Hypertensive patients were divided into two groups: hypertensives with and those without left ventricular hypertrophy. Plasma AM concentrations in hypertensive patients with left ventricular hypertrophy were significantly higher than in hypertensive patients without left ventricular hypertrophy (7.87±2.70 vs 5.74±1.65 fmol/mL, P r =.37, P =.009; r =.40, P =.004, respectively) and inversely correlated with carotid artery distensibility ( r =−.33, P =.02), whereas plasma AM concentrations were not correlated with intimal-medial thickness. These results suggest that the observed elevation of plasma AM in patients with essential hypertension with normal renal function may be partly related to cardiac hypertrophy and decreased carotid artery distensibility.

To evaluate autonomic nervous function by power-spectral analysis of heart-rate variability in salt-sensitive and non-salt-sensitive patients with essential hypertension under the conditions of low and high salt intakes.The blood pressures, heart rates, and electrocardiogram R-R intervals of 20 hypertensive patients were measured at intervals of 30 min during a 24 h period using a portable recorder (TM-2425) on the last day of the high- (250 mmol NaCl/day) and low-salt (25 mmol NaCl/day) diet periods. The patients whose 24 h average mean blood pressures were increased by more than 10% by the high salt intake were defined as salt-sensitive (n = 10); the other patients were considered non-salt-sensitive (n = 10). Power-spectral analysis of R-R intervals was performed to obtain the low-frequency component (0.05-0.15 Hz) and the high-frequency component (0.15-0.40 Hz).The average 24 h blood pressure in the salt-sensitive patients was increased by the high salt intake [by 19.1 +/- 2.0/9.1 +/- 0.8 mmHg (mean +/- SEM)], whereas the heart rate did not change. In contrast, the increase in 24 h blood pressure in the non-salt-sensitive patients caused by the high salt intake was not significant and the heart rate was decreased significantly by the high salt intake (by 5.9 +/- 1.4 beats/min). The high-salt diet increased significantly the high-frequency component and decreased the low-frequency:high-frequency component ratio both during the daytime and during the night-time for the non-salt-sensitive patients. In contrast, the high-frequency component and the night-time low-frequency: high-frequency component ratio of the salt-sensitive patients did not respond to dietary salt manoeuvres.Responses of the parasympathetic and sympathetic nervous systems to dietary salt manoeuvres were blunted in salt-sensitive patients. These altered modulations of the autonomic nervous system may contribute to the salt sensitivity of the blood pressure in patients with essential hypertension.

Objective To study the influence of seasons on blood pressure in ordinary circumstances. Design and methods We examined seasonal variations of home and 24h h ambulatory and office blood pressures in outpatients with essential hypertension. Office, home and ambulatory blood pressures of 50 outpatients with essential hypertension were recorded in 1993. The subjects were 26 women and 24 men, aged 59.3 ± 1.1 years (mean ± SEM). Office blood pressure was measured monthly by physicians. Home blood pressure was measured every day by the patients in the morning and evening. Ambulatory blood pressure was recorded every 30min in summer and in winter. The order of ambulatory blood pressure monitoring was randomized. The daytime and night-time blood pressures were calculated according to the true waking and sleeping times of the individual patients. Results Both office and home blood pressures showed significant seasonal variations. The winter-summer differences in office and home blood pressures were 4.7 ± 1.3/ 3.3 ± 0.9 and 5.9 ± 1.1/2.7 ± 0.6 mmHg, respectively. They were not influenced by the presence of antihypertensive agents. The winter-summer difference was also significant for daytime ambulatory blood pressure (3.5 ± 1.4/ 2.5 ± 0.8 mmHg), but not for night-time ambulatory blood pressure (-2.9 ± 1.7/ -1.2 ± 1.0 mmHg) or average 24 h blood pressure (1.5 ± 1.3/1.2 ± 0.7 mmHg). There were no significant differences in the waking and sleeping times between the two seasons. Conclusions Office, home and daytime ambulatory blood pressure levels were higher in winter than they were in summer in patients with essential hypertension. However, the seasonal variations in average 24 h blood pressure may be small because of the lack of changes in night-time blood pressure.

Abstract To investigate the effects of dietary sodium restriction from conception to adulthood on blood pressure and its regulatory mechanisms, male offspring were derived from inbreeding in spontaneously hypertensive rats fed a diet containing sodium of 175 μmol/g food (control) or 22 μmol/g (low sodium), which is the least sodium content for normal growth. While urinary sodium excretion was markedly less, the low sodium diet did not inhibit body growth and failed to blunt the development of hypertension. Neither plasma catecholamine concentration nor depressor response to hexamethonium was different between the two groups at any age examined (8, 12, and 20 weeks). Plasma renin concentration was not elevated, whereas urinary excretion of aldosterone was increased at any age in the low sodium group compared with that in the control group. Other sets of rats were fed a diet containing sodium of 175 μmol/g plus mefruside (a diuretic) of 0.001% in the same manner as in the other two groups. Urinary sodium excretion per creatinine was higher than in the other groups. The diuretic treatment inhibited body growth and suppressed adult blood pressure. While the sympathetic function was not affected, both plasma renin concentration and urinary excretion of aldosterone were elevated. These results indicate that dietary sodium restriction with the least sodium for normal growth from conception cannot blunt either the sympathetic nervous function or the development of hypertension in spontaneously hypertensive rats. Aldosterone appears to play an important role in maintaining sodium homeostasis under the dietary sodium restriction.

To examine the neural effects of antihypertensive drugs on renal blood flow, we measured blood flow and renal sympathetic nerve activity simultaneously in conscious spontaneously hypertensive rats aged 13 to 15 weeks. One to two days after surgery, intravenous administration of manidipine (calcium antagonist, n = 10), doxazosin (alpha 1-adrenergic receptor antagonist, n = 9), and clonidine (n = 7) lowered mean arterial pressure by at least 20% from baseline levels. Manidipine initiated a reduction of renal blood flow when mean pressure decreased by 20 +/- 2 mm Hg. At the maximal decrease in renal blood flow (mean pressure, -33 +/- 2 mm Hg), percent decrease in flow (-27 +/- 2%) significantly correlated with percent increase in renal nerve activity (+205 +/- 40%, r = -.878). Doxazosin began to decrease renal blood flow at a level of arterial pressure similar to that in manidipine treatment, whereas the maximal decrease in flow (-19 +/- 2%; mean pressure, -33 +/- 2 mm Hg; nerve activity, +225 +/- 44%) was significantly less than that in manidipine treatment. Although clonidine decreased arterial pressure and renal nerve activity, renal blood flow did not decrease even at the maximal decrease in mean pressure of 29 +/- 1 mm Hg. The addition of clonidine to manidipine treatment suppressed reflexly enhanced renal nerve activity and restored blood flow to the pretreatment level despite pronounced hypotension. These results clearly demonstrate that antihypertensive drugs with blocking action on renal nerve activity are capable of maintaining renal blood flow and that those associated with reflex-induced enhancement of nerve activity exert deteriorating effects on renal blood flow. Furthermore, a decrease in renal blood flow induced by calcium antagonists is mainly attributed to reflexly enhanced renal nerve activity.

The influence of a family history of hypertension on body mass index, serum lipids, uric acid, blood sugar and haematocrit was investigated in 579 young normotensives aged 19-35 years with or without a parental history of hypertension. Body mass index, total cholesterol, triglycerides and uric acid were significantly higher in offspring with a parental history of hypertension than in those without. There were no differences in blood sugar and haematocrit between the two groups. Multivariate analysis revealed that a parental history of hypertension influenced levels of body mass index, triglycerides and uric acid, independently of the level of blood pressure.

We examined the central action of NaCl on blood pressure using intracerebroventricular (i.c.v.) and intracisternal (i.c.) injections of hypertonic NaCl solution in conscious, unrestrained spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The dose-dependent pressor response produced by i.c.v. hypertonic NaCl was greater in SHR than in WKY rats, while the dose-related pressor action produced by i.c. NaCl did not differ between the two strains. The hyperresponsiveness to i.c.v. NaCl in SHR was abolished by pretreatment with an i.c.v. injection of the angiotensin II (ANG II) analogue 1-Sar, 8-IIeu ANG II. Both ANG II and a combination of ANG II and NaCl given by i.c.v. injection had a greater pressor response in SHR than in WKY rats, although both ANG II and phenylephrine given intravenously elevated blood pressure to the same extent in both strains. Furthermore, i.c.v. ANG II both with and without hypertonic NaCl caused dipsogenic behaviour which lasted longer in SHR than in WKY rats. This response to i.c.v. hypertonic NaCl without ANG II was not substantially different between the two strains. Intracisternal hypertonic NaCl did not induce drinking behaviour. These observations suggest that in the SHR, the third ventricle rather than the brain stem is a more sensitive area to NaCl. The brain renin-angiotensin system in the SHR may play an important role in this accelerated pressor response and may be responsible, at least to some extent, for the enhanced reaction to chronic oral salt loading.