The effects of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects.

AIM: Insulin resistance and visceral adiposity are predisposing factors for fatty liver disease. The main objectives of this study were (i) to compare the effects of caloric restriction (CR) alone or together with moderate-intensity aerobic exercise training (CR+EX) on liver enzymes, a surrogate marker of liver injury, in obese metabolic syndrome (MetS) subjects and (ii) to identify anthropometric, metabolic, cardiovascular and dietary predictors of changes in liver enzymes. METHODS: Sedentary men and women (n = 63), aged 55 ± 6 (s.d.) years with body mass index 32.7 ± 4.1 kg/m(2) and confirmed MetS, were randomized to 12-week CR, CR+EX or no treatment (Control). RESULTS: Weight loss averaged 7.6% in the CR and 9.1% in the CR+EX group (time effect, p < 0.001; group effect, p = 0.11); insulin sensitivity improved by 49 and 45%, respectively (both p < 0.001). Fitness (maximal oxygen consumption) increased by 19% in the CR+EX group only (p < 0.001). Alanine aminotransferase (ALT) levels decreased by 20% in the CR and 24% in the CR+EX group (time effect, both p < 0.001; group effect, p = 0.68); corresponding values for γ-glutamyltransferase (GGT) were -28 and -33%, respectively (time effect, both p < 0.001; group effect, p = 0.28). Reduction in abdominal fat mass (measured by DXA from L1 to L4) independently predicted ΔALT (r = 0.42, p = 0.005) and ΔGGT (r = 0.55, p < 0.001), whereas change in dietary saturated fat intake was independently associated with ΔALT (r = 0.35, p = 0.03). CONCLUSIONS: Reductions in central adiposity and saturated fat intake are key drivers of improvement in liver enzymes during lifestyle interventions. Exercise training did not confer significant incremental benefits in this study.

Plasma norepinephrine and dietary sodium intake in normal subjects and patients with essential hypertension.

To evaluate the relationship between sodium intake and the activity of the sympathetic nervous system in patients with essential hypertension, plasma catecholamine levels were measured in 49 essential hypertensive patients and 38 age-matched normal subjects under regular-, high-, and low-sodium diets (mean 24-hour sodium excretions; 116 +/- 8, 267 +/- 29, 31 +/- 7 mEq/day, respectively). The levels of plasma norepinephrine were significantly (p less than 0.01) higher in hypertensive patients than in normal subjects. However, they were significantly reduced by high-sodium intake and increased by low-sodium intake in both patients and controls. The percent decrease and change in the absolute plasma norepinephrine levels from low- to high-sodium states were greater in normal subjects than in the hypertensive patients. The results are interpreted as indicating that an abnormal relationship exists between sodium intake and the activity of sympathetic nervous system in patients with essential hypertension.

Familial hypertension, insulin, sympathetic activity, and blood pressure elevation.

This study evaluated the effects of a positive family history of hypertension (FH+) on the contributions of sympathetic nervous system (SNS) activity and insulin to blood pressure elevation (BPE). The study design was longitudinal and evaluated BP, body mass index (BMI), and fasting plasma insulin and norepinephrine (NE) levels for 10 years in 557 young, nonobese Japanese men who were normotensive at entry. FH+ was defined as hypertension in first-degree relatives as verified by historical records or direct determination. BPE was defined as a > or = 10% rise in systolic and diastolic BP over entry levels during the 10-year period. In the total group FH+ was noted in 16%, and BPE occurred in 18% of normotensive subjects. When evaluated by FH, the prevalence of BPE was 33% in FH+ compared with 16% in FH- (P<0.05). BP levels were greater both at entry and at year 10 in the FH+ group. The absolute increment in plasma NE over 10 years was greater in the BPE group than in those without BPE (P<0.01). Of note, the rise in plasma NE levels in BPE individuals was identical in FH+ and FH- subjects. Plasma insulin increments were also greater in normotensive subjects with BPE than in normotensive subjects without BPE. However, compared with NE, development of hyperinsulinemia was more pronounced in the FH+ subjects. The results indicate that SNS hyperactivity may be a less genetically determined predictor of hypertension than is hyperinsulinemia. Because SNS changes in this initially normotensive population appeared more closely related to the development of hypertension than to hyperinsulinemia, environmental rather than genetic factors may be the main determinant of early BPE in nonobese normotensive subjects.

Increased plasma norepinephrine in young patients with essential hypertension under three sodium intakes.

Increased sympathetic nerve activity may play an important role in the pathogenesis of essential hypertension. It is well known that both dietary sodium intake and age influence the plasma norepinephrine (NE) concentration. The present study was undertaken to evaluate the effects of age on sympathetic nerve activity in patients with essential hypertension and normal control subjects under low-, regular-, and high-sodium regimens (mean 24-hour sodium excretions: 30 +/- 4, 116 +/- 7,280 +/- 15 mEq, respectively). Plasma NE and epinephrine (E) were analyzed by trihydroxyindole methods after high-performance liquid chromatography separation. Subjects were categorized by age into young (less than or equal to 40 yrs), middle-aged (40-60 years), and old (greater than or equal to 60 years) subgroups. Mean plasma NE in hypertensive patients was significantly higher (p less than 0.01) than in normal subjects on each of the sodium regimens. In normal control subjects, there was a significant positive correlation between age and plasma NE with all three sodium intakes. However, no correlation was seen in hypertensive patients on any of the sodium regimens, because in the young subgroup of hypertensive patients the mean plasma NE was significantly higher than that of normal control subjects. These results suggest that the increased sympathetic nerve activity plays an important role in the pathogenesis of essential hypertension, especially in young patients.

Responses of active and inactive plasma renin and changes in urinary kallikrein and plasma prekallikrein to various conditions in normal subjects.

Little is known about changes in inactive plasma renin in various conditions or the in vivo activation mechanism of inactive renin. The effects of various factors known to stimulate or suppress renin release on active and inactive PRA were examined in normal subjects. Inactive PRA was determined as the difference between the total PRA after trypsin activation and active PRA. Concurrent measurements of urinary kallikrein excretion and plasma prekallikrein activity were performed to assess the possible role of renal or plasma kallikrein in in vivo activation of inactive renin. Short term stimulation with iv furosemide and ambulation, infusion of isoproterenol, and administration of captopril increased active PRA, but had little or no effect on inactive PRA. Sodium restriction and sodium loading, each for 4 days, induced parallel changes in active and inactive PRA. The administration of propranolol for 4 days decreased active PRA but did not change inactive PRA. There were no significant correlations between the changes in urinary kallikrein excretion and those in active PRA or in the proportion of active to total PRA after any short term treatments, except furosemide administration. Plasma prekallikrein activity was correlated with the proportion of active renin only during the long term sodium balance study. The present data suggest that the mechanisms ofr the control of inactive and active renin are different. Neither renal nor plasma kallikrein seems to be consistently involved in the in vivo activation of inactive renin.

The effect of aging on urinary kallikrein excretion in normotensive subjects and in patients with essential hypertension.

The effect of aging on urinary kallikrein excretion (UkalV) was investigated in 54 normal subjects, 11-88 yr old, and 37 patients with essential hypertension, 17-82 yr old. Urinary sodium, potassium, and aldosterone excretion (U(Ald)V) were also measured in these subjects. Urinary sodium and potassium excretion in both normal subjects and hypertensive patients did not significantly change with aging. In normal subjects, U(kal)V (r = 0.45; P less than 0.001) and U(Ald)V (r = 0.58; P less than 0.01) significantly decreased with increasing age. U(kal)V was positively correlated with U(Ald)V (r = 0.44; P less than 0.001). In contrast, the hypertensive patients had a significant decrease with age in U(Ald)V (r = -0.36; P less than 0.05), but no significant age-related change in U(kal)V. No significant correlation between U(kal)V and U(Ald)V was observed in the hypertensive patients. In individuals less than 60 yr old, there was no significant difference in U(kal)V values between normal subjects and hypertensive patients. Hypertensive patients more than 60 yr old excreted more urinary kallikrein than normal subjects of the same age group (P less than 0.05). In conclusion, the age-related decrease of U(kal)V in normal subjects may be due to the reduced activity of the renin-angiotensin-aldosterone system. It remains to be elucidated whether the absence of the age-related decrease in U(kal)V in hypertensive patients is related to the pathogenesis or pathophysiology of essential hypertension.

Prevalence of hyperinsulinemia in young, nonobese Japanese men.

OBJECTIVE: To clarify the prevalence of hyperinsulinemic subjects among young, nonobese, Japanese men, and to evaluate characteristics, in particular, of sympathetic nerve system activity and lipid fractions in hyperinsulinemic subjects. METHODS: Norepinephrine, plasma insulin, and lipid fractions were measured in 512 normotensive, 124 borderline hypertensive (BHT) and 88 established hypertensive (EHT) subjects, matched for age and body mass index, after they had fasted overnight. RESULTS: Hyperinsulinemia defined as mean fasting plasma insulin + 2SD in normotensives or more was found in 8% of all subjects (normotensive and hypertensive subjects, P = 0.018), 6% of normotensives, 10% of BHT (P = 0.28, versus normotensives), 18% of EHT (P = 0.005, versus normotensives), and 12% of hypertensives (P = 0.019, versus normotensives). The hyperinsulinemic (fasting insulin > or = mean + 2SD in normotensive) subjects had higher plasma norepinephrine levels in all blood pressure groups than did nonhyperinsulinemic (< mean + 2SD) subjects (normotensives P < 0.05, BHT P < 0.01, and EHT P < 0.05). Hyperinsulinemic normotensives had higher blood pressure levels than did nonhyperinsulinemic ones (P < 0.05); however, blood pressure levels in hyperinsulinemic BHT and EHT were similar to those in nonhyperinsulinemic subjects. Triglyceride in BHT and EHT was greater than that in normotensives (P < 0.05), and that in hyperinsulinemic subjects was greater than that in nonhyperinsulinemic subjects (P < 0.05). On the other hand, high-density lipoprotein cholesterol in hyperinsulinemic BHT and EHT was significantly lower than that in nonhyperinsulinemic BHT (P < 0.05) and EHT (P < 0.01). CONCLUSION: These results demonstrated that the prevalence of hyperinsulinemia among the present sample of young, nonobese, Japanese men was 12% and that the prevalence increased with blood pressure elevation. Furthermore, hypertriglyceridemia and sympathetic nerve hyperactivity appear to be related to hyperinsulinemia and the emergence of hypertension.

Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives.

The association of hypertension with insulin resistance has been reported. Troglitazone (CS-045) is a newly developed antidiabetic agent that enhances insulin sensitivity. Its antidiabetic effects have been confirmed in diabetic animals and patients. The present study was performed to evaluate whether the amelioration of hyperinsulinemia by troglitazone lowers blood pressure in essential hypertensives. Troglitazone was administered orally to 18 outpatients with essential hypertension complicated by mild diabetes at a dose of 200 mg twice a day for 8 weeks. Blood pressure was decreased from 164 +/- 3/94 +/- 2 mm Hg to 146 +/- 3 (P < .001)/82 +/- 3 (P < .05) mm Hg at 8 weeks of the treatment period. Pulse rate did not change. Fasting plasma glucose changed from 159 +/- 10 mg/dL to 144 +/- 14 mg/dL at 8 weeks (P < .05). Plasma insulin (IRI) levels changes from 9.1 +/- 1.2 microU/mL to 6.3 +/- 0.8 microU/mL at the endpoint of treatment (P < .1). Decrease in mean blood pressure from the control period to the endpoint of the treatment correlated significantly with decrease in IRI (r = 0.59, P < .05). In summary, troglitazone treatment induces improvement in both glucose metabolism and blood pressure control in essential hypertensive patients with diabetes mellitus. These results suggest that insulin resistance or plasma insulin level plays a role in the pathogenesis of essential hypertension.

Metabolic effects of long-term treatments with nifedipine-retard and captopril in young hypertensive patients.

The objective of this study was to clarify potential differences in the metabolism of glucose and lipids in a long-term treatment (for 5 years) for hypertension among nifedipine-retard and captopril in young, nonobese hypertensive men (HT). In 78 previously untreated HT who were given nifedipine-retard and in 81 HT given captopril, blood pressure (BP), pulse rate, blood glucose, and plasma insulin levels were measured every 30 min for 2 h after 75 g oral glucose ingestion, every year for 5 years. Twenty-six age- and body mass index (BMI)-matched normotensive men (NT) were measured for the same variables for 5 years. They were also measured for total cholesterol, triglyceride levels, and lipids fractions after an overnight fast, every year for 5 years without any kinds of lipid lowering agents. At 1 year after treatment with nifedipine-retard or captopril, BP decreased significantly, and the reductions in BP did not differ between HT treated with nifedipine-retard and captopril. In the entry period, fasting insulin (P < .05), the area under the curve (AUC) of insulin (P < .01), AUC of blood glucose (P < .05) after 75 g oral glucose ingestion, fasting total cholesterol (P < .05), and triglyceride levels (P < .05) in HT were significantly greater than those in NT. In HT treated with captopril, AUC of insulin (P < .01), AUC of blood glucose (P < .05), and total cholesterol (P < .05) decreased significantly after 1 year of treatment for HT, and triglyceride (P < .05) decreased significantly after the 2 year treatment. Although in HT treated with nifedipine-retard, AUC of insulin (P < .01) and AUC of blood glucose levels (P < .05) decreased significantly after 1 year of treatment, triglyceride and total cholesterol levels did not decrease throughout the 5 years. These results indicate that captopril has ameliorative effects in hyperinsulinemia or reduced insulin sensitivity, hypercholesterolemia, and hypertriglyceridemia starting at 1 year after the treatment for HT, whereas nifedipine-retard has an ameliorative effect in the metabolism of glucose but not in the metabolism of lipids. Therefore, ACE inhibitor has additional ameliorative effects on insulin sensitivity to the vasodilatory action.

Mechanisms mediating postprandial blood pressure reduction in young and elderly subjects.

The objective of this study was to clarify potential differences in hormonal, neurogenic and hemodynamic mechanisms mediating postprandial blood pressure (BP) reduction. In 12 age- and body mass index-matched young normotensive (NT) subjects, 21 elderly NT, 17 young hypertensive (EH) patients, and 32 elderly EH, we measured BP, blood glucose, plasma insulin (IRI), and norepinephrine (NE) levels before and every 30 min for 3 h after a 75 g oral glucose solution ingestion. Cardiac output (CO) and total systemic resistance (TSR) were also measured before and 1 h after oral glucose ingestion. Postprandial BP reduction, defined as 10% or more decline in mean BP was recognized in 3/12 (25%) young NT, 9/21 (43%) elderly NT, 5/17 (29%) young EH, and 20/32 (63%) elderly EH. The most consistent finding was that the IRI response to glucose was high in all subjects with postprandial BP reduction regardless of age or level of BP, although changes in blood glucose levels showed no major differences. The NE level was low in young and elderly NT with postprandial BP reduction, but in EH the level was not different. Increases in CO in elderly subjects with postprandial BP reduction was significantly less than that in subjects without postprandial BP reduction. In addition, the decrease in TSR in young subjects with postprandial BP reduction was significantly greater than that in subjects without postprandial BP reduction, while the decrease in elderly subjects was not different between the subjects with and without postprandial BP reduction. In conclusion, postprandial BP reduction in elderly EH appears to be associated with hyperinsulinemia independent of age and BP status. The vasodilator effects of insulin may contribute to postprandial BP reduction. A second conclusion is that impairment of sympathetic nervous system responses to insulin may also contribute to altered postprandial hemodynamic responses especially in EH, suggesting multiple mechanisms in origin of postprandial BP reduction.

Do reduced insulin sensitivity and dyslipidemia exist in borderline hypertensive patients?

To evaluate the relationship between insulin resistance, dyslipidemia, and blood pressure (BP), we measured BP, blood glucose, plasma insulin (INS) levels, total cholesterol (T-ch), and triglyceride after an overnight fast in 454 Japanese young, nonobese, nondiabetic factory workers, including 226 normotensive (NT), 120 borderline hypertensive (BHT), and 108 essential hypertensive (EHT) subjects. Age and body mass index were strictly matched among the three groups. Fasting INS and T-ch were greater in BHT > EHT > NT (BHT v NT, P < .05; EHT v NT, P < .05). We also recognized significantly positive correlations between T-ch and mean BP (R = 0.39, P = .021), and between fasting INS and mean BP (r = 0.56, P = .013). These results suggest that insulin resistance and dyslipidemia are associated with hypertension in its early stage.

Differences in insulin and sympathetic responses to glucose ingestion due to family history of hypertension.

To evaluate the relationship of metabolic and neural factors in familial hypertension, we examined blood pressure (BP), blood glucose, and plasma insulin and norepinephrine (NE) levels before and every 30 min for 120 min after glucose ingestion in six groups with 20 subjects each: normotensive subjects (NT) with and without a family history of hypertension; borderline hypertensive patients (BHT) with and without a family history of hypertension; and established hypertensive patients (EH) with and without a family history of hypertension. The changes in blood glucose were similar in the six groups. In the subjects with a positive family history of hypertension regardless of BP levels, the basal levels and changes in insulin levels after glucose ingestion were significantly greater than those in the subjects without a family history of hypertension (F = 13.32, P = .0001). In BHT and EH subjects, regardless of family history, changes in insulin were greater than in NT (F = 16.00, P = .0001). Basal levels and changes in plasma NE were higher in BHT and EH (F = 26.55, P = .0001) than NT and changes in plasma NE were greater in subjects with a family history than those in subjects without a family history (F = 18.32, P = .0001). Thus, abnormal insulin and NE responses to glucose appear to aggregate in subjects with a history of familial hypertension, regardless of the level of BP. Furthermore, the ratio of delta NE/ delta insulin (changes from basal to peak) in NT and BHT, and in subjects with a family history were significantly greater than in EH and in subjects without a family history. Thus, we demonstrated that concomitant abnormalities in the glucose-insulin regulatory system and the sympathetic nervous system characterize the early phase in the development of hypertension and these abnormalities have an apparent genetic basis.

Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population.

To evaluate the relationships between sympathetic nerve activity, insulin sensitivity, and blood pressure (BP) elevation, we examined BP, fasting blood glucose, plasma insulin, and norepinephrine (NE) levels in age- and body mass index (BMI)-matched 662 normotensive (NT) and 188 borderline hypertensive (BHT) subjects every year for 10 years. All measurements were taken in the supine position after an overnight fast. BP elevation (BP-E) during 10 years was defined as 10% or more elevation of mean BP when compared with BP at entry. BP-E was noted in 186 (28%) of NT and in 52 (28%) of BHT. Fasting insulin level at entry in BHT with BP-E was significantly greater than that in subjects without BP-E (P < .01), although fasting insulin level in NT with BP-E at entry was similar to that in NT without BP-E. Supine plasma NE level at entry period and year 10 in NT with BP-E was significantly greater than that in subjects without BP-E (P < .05, P < .01, respectively). Supine NE in BHT regardless of BP-E was significantly greater than that in NT at both entry and year 10. These results demonstrate that sympathetic nerve hyperactivity appears to precede hyperinsulinemia and resultant BP elevation in a young, nonobese Japanese population.

Changes in frequency of orthostatic hypotension in elderly hypertensive patients under medications.

To evaluate changes in frequency of orthostatic blood pressure (BP) reduction (orthostatic hypotension; OH) in elderly hypertensive patients (HT) before and after treatment for hypertension, we measured BP after supine for 10 min and standing position for 2 min, before and after treatment for 2 years by five kinds of antihypertensive drugs in 50 elderly normotensive subjects (NT) and each of 50 HT in double-blind study. Orthostatic hypotension was defined as 10% or more decline of supine mean BP, and the frequency of OH was in 27% of HT following BP reduction by any kinds of antihypertensive drugs. In conclusion, the reducing or normalized BP by treatment for hypertension in elderly HT decreases the prevalence of orthostatic hypotension.

Weight reduction and pharmacologic treatment in obese hypertensives.

This study was conducted to evaluate the mechanisms of weight loss-induced blood pressure (BP) reduction focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels, and to delineate the additional influence of antihypertensive drug therapy. Each of five groups of obese hypertensives were treated with the long-acting calcium channel blocker (CCB) amlodipine, the angiotensin converting enzyme (ACE) inhibitor enalapril with or without a weight reduction program, or a weight reduction program alone. The goal BP was less than 140/90 mm Hg for the pharmacologic treatment groups. The weight reduction program groups with or without pharmacologic treatment were divided into two groups; weight loss groups who succeeded in weight reduction (> or = 10%) and nonweight loss groups who failed in weight reduction (<10%) in the first 6 months. The final dose of CCB and ACE inhibitor were less in the combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups or in the pharmacologic and nonweight loss groups. In the weight reduction groups regardless of pharmacologic treatment, the percent reductions from baseline in plasma insulin, leptin, and norepinephrine (NE) were greater in the weight loss groups (> or = 10%) than in the nonweight loss groups (<10%). The reductions in plasma NE, insulin, and leptin were significantly greater and earlier in combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups. In ACE inhibitor groups, the reductions in plasma NE, in insulin, and especially in leptin were greater than the other groups. In the CCB alone group, reductions in insulin and leptin occurred, but there was no change in plasma NE. Reductions in insulin and leptin in CCB groups were less and occurred later than in the ACE inhibitor groups or the weight reduction alone group. These results show that weight loss associated with favorable metabolic improvements and these improvements are amplified when combined with pharmacologic treatment. Therefore, weight loss should be regarded as an essential component of any treatment program for obesity-related hypertension. A novel finding from this study is that ACE inhibition had a striking effect to lower plasma leptin. Suppression of sympathetic activity, insulinemia, and leptinemia appeared to play a role in the BP reduction accompanying weight loss.

Antihypertensive effects of the neutral endopeptidase inhibitor SCH 42495 in essential hypertension.

The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run-in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug.

Hormonal mechanisms in blood pressure reduction during hemodialysis in patients with chronic renal failure.

To elucidate the hormonal mechanisms of blood pressure (BP) reduction during hemodialysis in patients with chronic renal failure (CRF), we performed this study using 7 normotensive (NT) and 17 hypertensive (HT) patients who were strictly matched in age, body weight, body weight gain from the last HD, and duration of HD. Blood pressure, pulse rate, plasma norepinephrine (NE), and plasma dopamine levels were used as indices of sympathetic nerve activity, before, at 50% of hemodialysis (HD) and at 100% of HD (at the end of HD) on the third day after the last HD. As hemodialytic BP reduction was defined as BP decline of more than 10% in pre-HD mean BP, in normotensive patients with CRF, hemodialytic BP reduction was recognized in 0/7 (0%) at 50% of HD and 4/7 (57%) at 100% of HD, and in hypertensive patients it was recognized in 3/17 (18%) at 50% of HD and 4/17 (24%) at 100% of HD. Percentile changes in plasma NE levels increased slightly following hemodialysis in normotensive patients with hemodialytic BP reduction and in hypertensives without BP reduction, while those in normotensives without BP reduction and in hypertensives with BP reduction did not change. However, percentage changes in plasma dopamine (DA) levels decreased significantly at the end of HD (NT; p < 0.05, HT; p < 0.01) following hemodialysis in both normotensive and hypertensive patients with hemodialytic BP reduction, while changes in patients without BP reduction, percentage changes in DA did not change (patients with BP reduction vs. patients without BP reduction). In conclusion, hemodialytic BP reduction may be predisposed by abnormal sympathetic nerve responsiveness.

Sympathetic activity and body mass index contribute to blood pressure levels.

The purpose of this study was to clarify the relationships between obesity (BMI) and BP levels, leptin levels, sympathetic activity, and insulin sensitivity in a Japanese male population. In 912 young, non-diabetic, Japanese men with a wide range of BMI (16.5-33.6 kg/m2), blood pressure (BP), fasting plasma norepinephrine (NE), insulin and leptin levels were measured after an overnight fast. The cohort consisted of 603 normotensive and 309 hypertensive subjects. The study was carried out using a cross-sectional design. When the subjects were subdivided by tertile in relation to BMI, the 101 subjects in the heaviest group (BMI > 27.9 kg/m2) had a significantly higher systolic BP (p< 0.05) and pulse rate (p< 0.05) as well as higher NE (p< 0.01), insulin (p< 0.01), and leptin (p< 0.01) levels than 86 subjects in the leanest group (BMI < 22.2 kg/m2). In the whole cohort, BMI correlated with mean BP (p< 0.01), plasma NE (p< 0.05), insulin (p< 0.001) and leptin (p< 0.001). The mean BP correlated with BMI (p< 0.001), plasma NE (p< 0.01), insulin (p< 0.01) and leptin (p< 0.05). Plasma leptin levels correlated with fasting plasma insulin levels (p < 0.05), but not with plasma NE levels (NS). As analyzed by multiple regression analysis, only plasma NE (p< 0.05) and BMI (p< 0.001), but not plasma insulin levels, were significant, independent predictors of BP levels (r2=0.125, F= 10.51, p=0.0001). These results suggest that obesity (BMI) and heightened sympathetic nervous system activity contribute to BP elevation (hypertension).

Differences in mechanisms between weight loss-sensitive and -resistant blood pressure reduction in obese subjects.

This study was conducted to clarify the mechanisms involved in the sensitivity for blood pressure (BP) reduction in response to weight loss. In particular, we focused on the contributions of sympathetic nervous system activity and fasting plasma leptin and insulin levels to BP levels during weight loss in obese subjects with weight loss-sensitive and -resistant BP reduction. Sixty-one young, obese untreated hypertensive men (HT) and 52 obese normotensive men (NT) were enrolled in a weight loss program consisting of a low caloric diet and aerobic exercise over a 24-week period. At entry and at week 24, body mass index (BMI), BP, plasma norepinephrine (NE), leptin and insulin were measured. Successful weight loss and BP reduction were respectively defined as a more than a 10% reduction in BMI or mean BP from baseline at week 24. More than 60% of subjects in either group successfully achieved weight loss by this definition. The percentage of subjects who successfully achieved BP reduction was higher (64%) among those subjects who achieved weight loss than among those who did not (22%). Plasma NE level at entry in subjects who failed to achieve BP reduction despite weight loss was significantly higher than that in subjects who succeeded in BP reduction. Plasma leptin and insulin levels were similar between subjects with and without BP reduction. In addition, the absolute decrement and percent decrement in plasma NE in subjects who succeeded in BP reduction were significantly greater than those in subjects who failed to reduce their BP. Absolute and percent decrements in plasma leptin and insulin were similar in both groups. These results suggest that individuals who are resistant to weight loss-induced BP reduction have more sympathetic overactivity both at the outset of and during weight loss.

Pilot study of a new angiotensin II receptor antagonist, TCV-116: effects of a single oral dose on blood pressure in patients with essential hypertension.

After a 1-week placebo control period, six hypertensive patients (mean age, 67 years) each received single doses of 1, 2.5, and 5 mg of TCV-116 at 2- to 3- day intervals. Systolic and diastolic blood pressures were significantly lower after the final dose (5 mg) of TCV-116 than on the last day of the placebo period. Blood pressures were decreased after each dose of TCV-116 in a dose-dependent fashion from 2 hours after administration and reached a nadir at 4 to 6 hours. After 2.5 and 5 mg of TCV-116, the hypotensive effect was sustained for 24 hours. Pulse rate did not change significantly. Plasma renin activity and angiotensin I levels increased in a dose-dependent fashion after TCV-116, but the changes were not significant. No changes were noted in plasma aldosterone or angiotensin II levels. One patient reported mild light-headedness after 5 mg of TCV-116. No other side effects or abnormal laboratory tests results were noted. It appears that TCV-116 is a safe and effective antihypertensive agent.