Search

Previous studies have reported that the number of pregnancies and childbirths affected the risk of cardiovascular diseases (CVDs). However, the influence of reproductive history on hypertension and obesity, which are important risk factors for CVDs, is still unclear. Moreover, this association may vary depending on menopausal status. We evaluated the association of reproductive history with hypertension and obesity using a large cross-sectional dataset from the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). At the baseline survey, physical data, blood samples, and self-reported health questionnaires were collected. Participants with insufficient data were excluded, and 24,558 women from eight study regions were included in this study. Logistic regression analysis was conducted to evaluate the association of reproductive history with hypertension and obesity using multivariable-adjusted odds ratios. In premenopausal women, childbirth showed a generally protective effect on hypertension but not on obesity. In postmenopausal women, childbirth was positively associated with obesity and hypertension but not with hypertension after adjusting for BMI. In conclusion, reproductive history was associated with hypertension and obesity in a large Japanese population, and this association differed between premenopausal and postmenopausal women., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

There are few studies examining the association between homocysteine (Hcy) level and the risk of hypertension with consideration for folate and vitamin B 12 as related to Hcy level. We simultaneously examined the associations of plasma levels of Hcy, folate, and vitamin B 12 , and dietary folate intake with the prevalence of hypertension. Participants included 1046 men and 1033 women (mean age ± standard deviation: 56.0 ± 8.9 years) in the Japan Multi-Institutional Collaborative Cohort Study. Dietary folate intake was estimated using a validated food frequency questionnaire. Hypertension was defined based on measured blood pressure and use of antihypertensive medication. A total of 734 participants (35.3%) had hypertension. Multivariate-adjusted odds ratios of hypertension for the highest quartile group of Hcy were 2.36 (95% CI 1.41-3.96) in men and 1.86 (95% CI 1.11-3.11) in women, as compared with the lowest group (P for trend = 0.014 and 0.005, respectively). Dietary folate intake was not correlated with hypertension in both men and women (P for trend = 0.099 and 0.703, respectively). Plasma vitamin B 12 was positively associated with hypertension only in women (P for trend = 0.027). Plasma Hcy level was positively linked with hypertension after controlling for covariates, including folate and vitamin B 12 .

The aim of this study is to show the combined effect of weight gain within normal weight range in adulthood and parental HT on the prevalence of HT. The study subjects were 44,998 individuals (19,039 men and 25,959 women) with normal weight (body mass index [BMI] 18.5-24.9) aged 35-69 years who participated in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. They were categorized into six groups by weight gain from age 20 years (<10 kg, and ≥10 kg) and by the number of parents having HT (no parent, one parent, and both parents). Odds ratios for HT were estimated after adjustment for age, sex, current BMI, estimated daily sodium intake, and other confounding factors. The prevalence of HT (31.5% in total subjects) gradually increased with greater weight gain from age 20 years and with greater number of parents with HT. Subjects who gained weight ≥10 kg and having both parents with HT showed the highest risk of having HT compared with those who gained weight <10 kg without parental HT (59.8% vs. 24.9%, odds ratio 4.25, 95% CI 3.53-5.13 after adjustment). This association was similarly observed in any category of age, sex, and BMI. Subjects who gained weight within normal range of BMI and having one or both parent(s) with HT showed the higher risk of having HT independent of their attained BMI in their middle ages. Thus, subjects having parent(s) with HT should avoid gaining their weight during adulthood, even within normal range of BMI, to reduce the risk of having HT.

Brief exposure to passive smoking immediately elevates blood pressure. However, little is known about the association between exposure to passive smoking and chronic hypertension. We aimed to examine this association in a cross-sectional study, after controlling multiple potential confounders.Participants included 32,098 lifetime nonsmokers (7,216 men and 24,882 women) enrolled in the Japan Multi-Institutional Collaborative Cohort Study. Passive smoking was assessed using a self-administered questionnaire. The single question about exposure to passive smoking had five response options: "sometimes or almost never," "almost every day, 2 hours/day or less," "almost every day, 2 to 4 hours/day," "almost every day, 4 to 6 hours/day," and "almost every day, 6 hours/day or longer." Hypertension was defined as any of the following: systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive medication. Multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) for hypertension were estimated by exposure level to passive smoking using unconditional logistic regression models.The multivariate-adjusted OR for hypertension in those exposed almost every day was 1.11 (95% CI: 1.03-1.20) compared with those exposed sometimes or almost never. The OR for a 1-hour per day increase in exposure was 1.03 (95% CI: 1.01-1.06, Pfor trend = .006). This association was stronger in men than in women; the ORs were 1.08 (95% CI: 1.01-1.15, Pfor trend = .036) and 1.03 (95% CI: 1.00-1.05, Pfor trend = .055), respectively.Our findings suggest importance of tobacco smoke control for preventing hypertension.

Elderly patients have much more complex QOL problems as compared with young or middle-aged patients because of their specific social and psychological circumstances, as well as their multiple organ disorders. Specifically, one should take into account, in the treatment of hypertension in the elderly with respect to QOL, the effect of antihypertensive drugs on the cognitive function and the influence on other diseases or hypertensive complications. Most of the currently used antihypertensive drugs are shown to be inert to the cognitive function. In order to maintain or improve QOL of elderly hypertensive patients, adequate drugs should be selected individually. In general, ACE inhibitors, long-acting Ca antagonists are the drugs of choice for the treatment of hypertension in the elderly with regard to QOL.

Higher pulse pressure is associated with higher cardiovascular risk. We investigated the relationship between pulse pressure and known metabolic risk factors in hypertensive patients who had not experienced stroke or myocardial infarction. In a multicenter cross-sectional survey made in 1995, we registered 939 hypertensive patients aged > or = 50 years. Of these, 734 had never experienced stroke or myocardial infarction. We divided these 734 patients into two groups based on the value of their pulse pressures: 396 patients with a pulse pressure > or = 60 mmHg, and 338 patients with a pulse pressure<60 mmHg. The average pulse pressure value was 72 +/- 12 mmHg in the former group, and 49 +/- 8 mmHg in the latter group. The former group exhibited advanced age, a higher women-to-men ratio, lower high-density lipoprotein (HDL) cholesterol, and higher systolic and lower diastolic blood pressure. Diabetes mellitus (DM) and left ventricular hypertrophy were more frequently noticed in the former group than in the latter group. The prevalence of hyperlipidemia, however, was similar in the two groups. The association of pulse pressure with DM and low HDL cholesterol was statistically significant by multiple logistic analysis adjusted for age, sex, and other known cardiovascular risk factors. In conclusion, pulse pressure increases with advancing age. DM made a substantially larger contribution to the increase in pulse pressure than hyperlipidemia.

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.

The aim of this study was to analyze the treatment of elderly hypertensive patients by Japanese physicians specializing in hypertension. We enrolled 939 patients with hypertension who were treated in the outpatient clinics of 11 hospitals in 1995; 793 of these patients (388 men and 405 women; mean age, 66.6+/-9.0 years) received follow-up examinations in 1996, and the data on these patients was used for the present analysis. Blood pressure (BP), body mass index, lifestyle, and laboratory data were analyzed in all patients. The average BP was 143+/-16/81+/-10 mmHg in 1995 and 142+/-15/80+/-10 mmHg in 1996. The patients whose baseline BP was at the level of Grade 2 or 3 in the WHO-ISH classification (n=117) were characterized by a higher women-to-men ratio, higher age, a higher serum total cholesterol concentration, and higher QRS voltage. In these patients, from 1995 to 1996, the average BP significantly decreased, whereas fasting plasma glucose, serum total cholesterol and serum creatinine concentrations showed only negligible changes. In 220 patients (28%), BP was <140/<90 mmHg at both the initial and the follow-up examinations, whereas 351 patients (44%) were hypertensive in both 1995 and 1996. Thirty-three percent of the patients were smokers. More smokers than nonsmokers had had prior cardiovascular events, diabetes mellitus, or overt proteinuria. In conclusion, the average BP level among the patients treated by Japanese physicians specializing in hypertension was somewhat higher than that recommended by WHO-ISH Guidelines (1999). Patient education to control lifestyle-related risk factors, particularly to stop smoking, should be emphasized.

Although calcium-channel blockers and angiotensin-I-converting enzyme inhibitors are often used for treatment of hypertension in the elderly in Japan compared to those in the United States and in European countries, there have been few investigations on the prognosis of the elderly receiving these antihypertensive treatments. The Research Group for "Guidelines on the Treatment of Hypertension in the Elderly" collaborated with the Comprehensive Research Projects on Aging and Health group of the Ministry of Health and Welfare of Japan in performing a 3-year survey on the outcome of 700 hypertensive elderly outpatients (> or = 60 years) receiving treatment of antihypertensive drugs. Antihypertensive drugs including dihydropyridine-type calcium channel blockers, beta blockers, angiotensin-I-converting enzyme inhibitors, diltiazem, diuretics and old-type antihypertensives (hydralazine, budralazine, and centrally acting drugs such as clonidine, methyldopa and guanabenz) were administered to 71.3%, 30.4%, 26.2%, 14.0%, 8.6%, and 6.4% of the 642 elderly patients surveyed for three years, at the time of registration, respectively. Morbidity and mortality rates of total cerebro-cardiovascular diseases, stroke, and heart diseases, were 27.6 and 7.81/1,000 patient-years, 15.1 and 3.6/1,000 patient-years, 10.4 and 4.2/1,000 patient-years, respectively. These results were similar or even better than those of megatrials of antihypertensive treatments for elderly patients in Europe and United States. After adjustment for potential confounding factors, multiple logistic analysis revealed that a past history of ischemic heart disease, use of the old-type antihypertensive drugs, male gender, and diastolic high blood pressure were independent risk factors for the morbidity of cerebro-cardiovascular diseases taking the group of non-cerebro-cardiovascular disease as the reference group. We also identified 22 cases of newly occurred malignancies including 7 fatal cases. However, none of the antihypertensives was significantly related to the occurrence of malignancies. These results lead support to the tendencies in the use of antihypertensive drugs in Japan.

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.

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.

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.

We evaluated the renal effects of the new angiotensin II type 1 (AT ) receptor antagonist, HR 720, in the stroke-prone spontaneously hypertensive rat. Rats were treated with either vehicle, HR 720, MK-954 (a selective AT1 receptor antagonist) or enalapril for 6 weeks. Blood pressure was decreased to a similar extent by HR 720, MK-954 and enalapril (203 +/- 4, 202 +/- 5 and 190 +/- 4 vs. 247 +/- 4 mm Hg for control). Urinary protein secretion was also decreased (5.2 +/- 0.3, 5.3 +/- 0.2 and 5.5 +/- 0.6 vs. 25.2 +/- 4.6 mg/100g/24h). The glomerular hypertensive change was improved in each drug-treated group (2.0 +/- 0.2, 3.3 +/- 0.3 and 1.6 +/- 0.1 vs. 17.6 +/- 1.5%; p < 0.0001). These results show that, in addition to its antihypertensive effect, HR 720 has a beneficial effect on renal function.

To assess how elderly Japanese hypertensive patients are treated by specialists, we conducted a cross-sectional survey. A total of 1,163 outpatients aged 50 years or older were studied. Hypertension was diagnosed in 939 of these patients, and 827 were receiving drug therapy. The average blood pressure during therapy was 143 +/- 16/81 +/- 10 mmHg. In patients aged 70 years or older, systolic blood pressure during antihypertensive therapy was significantly higher (p < 0.01) and diastolic blood pressure was significantly lower (p < 0.01) than the corresponding values in those aged 50 to 59 years or 60 to 69 years. The calculated mean blood pressures were similar in the different age groups. The rate of monotherapy in the patients aged 70 years or older was 58.8%, which was significantly higher (p < 0.01) than the rates of monotherapy in the other age groups. Calcium channel blockers were prescribed in about 80% of patients, irrespective of age or comorbidity. Of the patients receiving calcium channel blockers, 43.5% were treated with monotherapy. This rate significantly (p < 0.01) increased with advancing age. Diastolic blood pressures were significantly lower (p < 0.05) in patients with stroke and in those with ischemic heart disease, diabetes mellitus, or dyslipidemia, as compared with patients with no comorbidity. Among patients aged 70 years or older, the difference in systolic blood pressure between those with ischemic heart disease and those with no comorbidity was not significant. Blood pressure in elderly hypertensive patients was reduced to a level similar to that in younger patients. The target blood pressure was influenced by the presence of comorbidity. Furthermore, specialists showed a high preference for the use of calcium channel blockers in the management of hypertension.

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP > 90 approximately 10 mmHg. Systolic BP < age + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/< 90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

The objective of this investigation was to evaluate the role of hypertension in endothelial function, changes in which are known to be an early event of atherosclerosis. We assessed endothelial function in 13 subjects with normal blood pressure and 13 subjects with essential hypertension who had never been treated for hypertension or hyperlipidemia and who had no history of smoking or coronary or cerebrovascular disease. B-mode ultrasonography was used to measure the diameter of the brachial artery. Endothelium-dependent dilatation was assessed as the change in diameter of the artery during reactive hyperemia. Endothelium-independent dilatation was evoked, as a control, by sublingual administration of isosorbide dinitrate. Despite similar ages and lipid and glucose levels in the study groups, endothelium-dependent dilatation was less in patients with hypertension (13.1% +/- 1.6%) than in subjects with normal blood pressure (18.5% +/- 1.9%) (p < 0.05), whereas isosorbide dinitrate-induced changes were similar. Systolic and diastolic blood pressure were significantly correlated with endothelium-dependent vasodilatation (r = -0.57 and r = -0.53, respectively) but not with the change by isosorbide dinitrate. These results suggest that endothelial dysfunction exists in patients with hypertension and precedes overt atherosclerotic disease.

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.

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.

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.

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.

Objective: To investigate the effects of central amino acid neurons on the antihypertensive action of a newly developed angiotensin II type 1 receptor (AT1) antagonist, CV 11974., Materials and Methods: We measured the release of various amino acids in the rostral ventrolateral medulla using the brain microdialysis technique. A microdialysis probe was inserted into the exposed rostral ventrolateral medulla in male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaesthetized with urethane. Mean arterial pressure and the release of amino acids (glutamate, glycine, glutamine, taurine and gamma-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 mu g/kg per min) or vehicle., Results: In SHR, CV 11974 decreased mean arterial pressure (-40 +/- 6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 +/- 83%) and gamma-aminobutyric acid (363 +/- 71%) in the rostral ventrolateral medulla, whereas intravenous nitroglycerin produced a decrease in mean arterial pressure (-35 +/- 4 mmHg) without changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant decreases in mean arterial pressure (CV 11974, -18 +/- 5 mmHg; nitroglycerin, -20 +/- 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or gamma-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furthermore, the use of a specific antagonist of glycine or of the gamma-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT1 antagonist in SHR., Conclusion: The present results suggest that the release of the inhibitory amino acids glycine and gamma-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT1 receptor antagonist in the genetic hypertensive rat model.

The effects of long-term monotherapy with cilazapril, an angiotensin-converting enzyme inhibitor, on blood pressure, glucose tolerance, and serum lipid profiles were prospectively investigated in 66 patients with hypertension: 23 with normal glucose tolerance and 43 with glucose intolerance (including 9 patients with non-insulin-dependent diabetes mellitus). The levels of plasma glucose, serum insulin, serum lipids, glycated hemoglobin A(lc) (Hb A(lc)), and fructosamine were determined before and during long-term (mean +/- SD, 26.2 +/- 1.2 weeks) therapy with cilazapril. A 75-g oral glucose tolerance test was performed before and during treatment. Significant reductions in both systolic and diastolic blood pressures in both patient groups were maintained during the study. Neither fasting nor post-glucose load venous plasma glucose levels were altered in either group of patients, and no patient with normal glucose tolerance developed diabetes mellitus during the study. There was no significant change in the insulinogenic index (delta serum insulin/delta venous plasma glucose at 30 minutes post-glucose load) in either group, and glucose intolerance was slightly improved with significant reductions (P < 0.01) in Hb A(lc) and fructosamine in the patient group with impaired glucose tolerance. Serum total cholesterol (TC), low-density lipoprotein cholesterol, and triglyceride levels were significantly (P < 0.01) decreased and high-density lipoprotein cholesterol levels increased in patients with hypercholesterolemia (TC levels > or = 5.69 mmol/L). These results suggest that long-term cilazapril therapy may improve glucose and lipid metabolism in hypertensive patients with impaired glucose tolerance. Cilazapril also appears to be useful as an antihypertensive agent for hypertensive patients with either impaired glucose tolerance or hypercholesterolemia.

The renin-angiotensin system plays an important role in blood pressure regulation. Angiotensinogen, which is mainly produced in the liver, is a unique component of the renin-angiotensin system, because angiotensinogen is only known as a substrate for angiotensin I generation. It is unclear whether circulating angiotensinogen is a rate-limiting step in blood pressure regulation. Recent findings of genetic studies and analyses suggest that the angiotensinogen gene may be a candidate as a determinant of hypertension. To test the hypothesis that angiotensinogen may modulate blood pressure, we transfected antisense oligonucleotides against rat angiotensinogen into the rat liver via the portal vein using liposomes that contain viral agglutinins to promote fusion with target cells, a technique that has been reported to be highly efficient. Transfection of antisense oligonucleotides resulted in a transient decrease in plasma angiotensinogen levels in spontaneously hypertensive rats from day 1 to day 7 after the injection, consistent with the reduction of hepatic angiotensinogen mRNA. Plasma angiotensin II concentration was also decreased in rats transfected with antisense oligonucleotides. Moreover, a transient decrease in blood pressure from day 1 to day 4 was observed, whereas transfection of sense and scrambled oligonucleotides did not result in any changes in plasma angiotensinogen level, blood pressure, or angiotensinogen mRNA level. Overall, our results demonstrate that transfection of antisense oligonucleotides against rat angiotensinogen resulted in a transient decrease in the high blood pressure of spontaneously hypertensive rats, accompanied by a decrease in angiotensinogen and angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)

We conducted a cross-sectional study of elderly outpatients with hypertension to examine the relationship between quality of life (QOL) scores and social background factors. The subjects consisted of 516 outpatients (267 females), age of 60 or over, at nine clinics of major hospitals which participated in the National Cardiovascular Center Research Project. The perceived QOL was evaluated by the QOL scale originally based on Japanese patients with cardiovascular diseases. The scale consisted of the following 5 subscales; difficulty due to disease, psychological stability, independence, satisfaction in daily living and vitality. The background factors included family structure, socioeconomic factors and work status, and physical activity of daily living (ADL). After adjusting for age, sex, administered drugs and complicating conditions such as ischemic heart disease and/or apoplexy, a significant odds ratio of a low score of difficulty due to disease, psychological stability, satisfaction in daily living and vitality was found in the impaired physical ADL group with low socioeconomic class, and a significant odds ratio of low score of independence were found in the impaired physical ADL group who had lost jobs due to illness and had no children.

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.

To detect genetic predisposing factors for hypertension, we screened the genome of the spontaneously hypertensive rat (SHR). We determined the genotypes of all F2 rats at polymorphic sites between the two strains, using the DNA of F2 rats derived from mating of SHR and Wistar-Kyoto rats (WKY). Cosegregation analysis was conducted to assess whether the genotypes of polymorphic markers associate with any phenotypic parameters such as directly measured blood pressure, heart rate or body weight. All measurements in F2 rats were performed at 15 weeks of age. Two polymorphic markers on chromosome 18 cosegregated with body weight. Gap junction protein (heart connexin 43) gene showed the most significant association with body weight as a recessive trait, but no association was noted with other parameters. We conclude that the gap junction protein locus is a new candidate for the determinant gene of body weight in SHR.

Recent epidemiological intervention studies demonstrated the effectiveness of antihypertensive treatment in the elderly and the indications of antihypertensive treatment have been extended to include a higher age group. However, because elderly hypertensive patients have different background characteristics from younger cases, thus there is considerable difficulty in evaluating the quality of life. The elderly have a lowered level of quality of life prior to the treatment due not only to the age-related physiological reduction in capacity and various chronic medical complications but also to a depressive tendency owing to inevitable financial and social losses. Therefore, extreme attention should be directed to avoid further worsening of the quality of their life by antihypertensive treatment which is one kind of intervention for patients in this particular age group. It is true that the side effect of antihypertensive drugs is one of the most potent worsening factors of the quality of life, but each drug has effects of its own other than side effects on the quality of life. In this article, we reviewed our own experience and reports from overseas in the evaluation of quality of life in the hypertensive elderly.

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.

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.

To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.

An association study of the polymorphism of the angiotensinogen gene, consisting of T-->C transition at nucleotide 704 in exon 2, with essential hypertension in the Japanese population was performed by restriction fragment length polymorphism (RFLP). The allele which contained the Tth 111-I restriction site in the presence of C transition was designated 'a' and the allele that lacked restriction site was designated 'A'. The frequency of aa genotype in our normotensive group was higher than the previously reported values in Caucasians. In spite of the high frequency of the aa genotype in Japanese, the aa genotype was significantly more frequent in 108 hypertensives than in 104 normotensive subjects compared with the two other genotypes (P = 0.009). These results suggested that this molecular variant of the angiotensinogen gene may be a preserved inherited predisposition for essential hypertension in various ethnic groups, including Caucasians and Japanese.

Insulin resistance and glucose intolerance have been suggested to be involved in the pathogenesis of various cardiovascular diseases. We examined the role of glucose intolerance in cardiac performance and cardiac hypertrophy in 33 patients with essential hypertension (28 to 71 years of age, mean +/- SD: 53 +/- 13 years) who had never been treated. Patients with obesity (body mass index > 30 kg/m2) or overt diabetes were excluded. Plasma glucose and insulin were measured after oral administration of 75 g glucose. The incremental areas of glucose and insulin were used as indices of glucose intolerance and insulin resistance, respectively. Patients with impaired glucose tolerance according to World Health Organization criteria (n = 12) showed a significantly higher ratio of peak velocity during atrial contraction to early left ventricular filling phase (A/E ratio) than those with normal glucose tolerance (n = 21) despite similar age, blood pressure, and left ventricular mass index. By regression analysis, left ventricular mass index positively correlated with systolic blood pressure (r = .392, P < .05) but not with any parameters of glucose and insulin metabolism. A/E ratio determined by a Doppler system significantly correlated with age ( r = .776) and fasting and peak levels and incremental area of plasma glucose (r = .529, r = .468, and r = .634) but not with those parameters of insulin. In contrast, ejection fraction was not related to blood pressure, glucose tolerance, or insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The role of the brain renin-angiotensin system in the pathogenesis of genetic hypertension was evaluated using a specific non-peptide angiotensin II type-1 receptor antagonist, TCV-116. 2. CV-11974 (active metabolite of TCV-116) was acutely injected either intravenously (i.v.) or intracerebroventricularly (i.c.v) in male spontaneously hypertensive rats (SHR; 12 week old). In separate groups of nephrectomized and sham-operated SHR, graded doses of CV-11974 were administered either i.v. or i.c.v. for 2 days using an osmotic minipump. In another group, the effects of nephrectomy on the depressor effect of chronic treatment with CV-11974 were investigated. Haemodynamics at three points: before infusion, before nephrectomy and 48 h after nephrectomy, were monitored. 3. Acute i.c.v. injection of CV-11974 decreased blood pressure in the presence of the kidney. Prolonged i.c.v. administration of the drug for 2 days decreased blood pressure even at the lowest dosage, which had no hypotensive effects when given i.v. The hypotensive effect of centrally administered CV-11974 was noted even 48 h after bilateral nephrectomy. 4. These results suggest that the brain renin-angiotensin system has a primary role in the maintenance of hypertension after eliminating the circulating renin-angiotensin system in SHR.

The effects of long-term monotherapy with terazosin, an alpha-1 blocker, on blood pressure, glucose tolerance, and serum lipid profiles were prospectively investigated in 53 hypertensive patients: 19 with normal glucose tolerance (NGT) and 34 with impaired glucose tolerance (IGT). The plasma glucose, serum lipids, fructosamine, and glycosylated hemoglobin A1c (HbA1c) levels were determined before and during long-term (6 months) therapy with terazosin. A 75-g oral glucose tolerance test was performed before and during long-term terazosin therapy. Significant falls in both systolic and diastolic blood pressure in both patient groups were maintained during the long-term therapy with terazosin. Neither fasting nor postglucose-load venous plasma glucose levels were altered in either group of patients, and diabetes mellitus did not develop in any patient with NGT during the study. There was no significant change in the insulinogenic index (delta IRI/delta BS at 30 minutes after glucose load) in either patient group. In patients with IGT, glucose intolerance was slightly improved with significant reductions in HbA1c and fructosamine during terazosin therapy. Serum total cholesterol (TC) and triglyceride levels were significantly decreased in patients with IGT. In addition, TC and low density lipoprotein (LDL) cholesterol were significantly decreased in patients with hypercholesterolemia (TC > 220 mg/dL). These results suggest that long-term therapy with terazosin may improve glucose and lipid metabolism in hypertensive patients and terazosin seems to be an antihypertensive agent with beneficial effects for hypertensive patients with either dyslipidemia or impaired glucose metabolism.

To study the effects of age and hypertension on autonomic nervous function with passive postural change, we examined 31 normotensive subjects (25 to 85 years old) and 31 hypertensive patients (21 to 71 years old) without any cardiac disease, diabetes mellitus, or neurological disorders. Subjects were passively placed in a 60 degrees head-up tilting position after 15 minutes in the supine position. Autonomic nervous function was evaluated by frequency domain analysis of heart rate with the autoregressive method. Using low-frequency (0.1 Hz) and high-frequency (0.25 Hz) peaks, the ratio of low- to high-frequency power (L/H) was calculated as an index of sympathetic activity and the ratio of high to total power (%HF) as that of parasympathetic activity. With the patient in the supine position, total power spectral density declined logarithmically with age in normotensive subjects and hypertensive patients, but %HF and L/H showed no changes. In response to passive tilting, L/H was increased and %HF was decreased in the normotensive subjects, and these responses declined with age logarithmically. In contrast, hypertensive patients exhibited less autonomic response to postural change regardless of age. These results suggest that autonomic neural response to tilt is decreased with age; however, attenuation of the response by hypertension is not associated with an increase in age.

Although the activity of the renin-angiotensin system is known to decrease with age, the antihypertensive efficacy of angiotensin-converting enzyme (ACE) inhibitors has been demonstrated in the elderly. To examine the role of the renin-angiotensin system in hypertension in the elderly, we evaluated the antihypertensive response to enalapril and to TCV-116, an angiotensin II type-1 receptor antagonist, in elderly patients with essential hypertension. A single oral dose of enalapril (10 mg) increased plasma renin activity (PRA) and reduced the angiotensin II concentration, whereas a single oral dose of TCV-116 (4 mg) increased both PRA and the angiotensin II concentration. Blood pressure was significantly reduced by these drugs from 4 h after administration. Basal levels of PRA and angiotensin II declined with age. However, the changes in blood pressure produced by either TCV-116 or enalapril did not correlate with age. These results suggest that the activity of the renin-angiotensin system in plasma declines with age, and that the extrarenal renin-angiotensin system may play a role in hypertension in the elderly.

We established an efficient and nontoxic in vivo gene transfer method mediated by the Sendai virus (hemagglutinating virus of Japan [HVJ]), liposomes, and nuclear protein. In this study, to produce a hypertensive model rat that is dependent on human renin, the human renin gene was introduced into adult rat liver by our efficient in vivo gene transfer method using HVJ and liposomes (HVJ-liposomes). The rats treated with HVJ-liposomes containing the human renin gene showed a significant elevation of blood pressure for 6 days compared with control rats, which received injections of HVJ-liposomes without the human renin gene. On day 5 after the transfer, human active renin as well as angiotensin II were found in the plasma of rats in which the human renin gene was introduced. Moreover, the blood pressure of these rats was significantly correlated with the plasma levels of human active renin and angiotensin II. To confirm that the elevated blood pressure was due to the expression of the human renin gene, we administered a newly developed specific human renin inhibitor, FK 906. The elevated blood pressure was normalized by the intravenous administration of this drug. These data indicate that this hypertensive rat was produced by the in vivo transfer of the human renin gene into rat liver and that the expressed human renin cleaved rat substrate (angiotensinogen). This hypertensive rat produced by in vivo gene transfer should be useful in further studies on 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.

The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.

The antihypertensive efficacy of a newly developed orally active human renin inhibitor (FK906) was evaluated in 14 patients with essential hypertension aged 40 to 83 years (mean, 64 years). After a 1-week placebo run-in period, 25 mg of FK906 was given twice daily; this was increased up to 100 mg twice daily until sufficient blood pressure reduction was obtained. No adverse effects were observed in any patients. Supine blood pressure was decreased from 169 +/- 3/97 +/- 1 mmHg to 153 +/- 5/87 +/- 3 mmHg at 25 mg twice daily (n = 14), to 142 +/- 5/78 +/- 3 mmHg at 50 mg twice daily (n = 12), P < 0.01), and to 137 +/- 10/77 +/- 8 mmHg at 100 mg twice daily (n = 6, P < 0.01). The hypotensive effect was sustained over 24 hours. Pulse rate did not change. Plasma renin activity and angiotensin I were decreased after FK906 administration only in patients with increased plasma renin activity. The hypotensive effects of FK906 were not correlated with baseline plasma renin activity. Suppression of the noncirculating tissue renin-angiotensin system may account for the hypotensive action of FK906. The results suggest that FK906 is a promising antihypertensive drug in patients of all ages and with different plasma renin levels.

Molecular cloning of cytochrome P450(11 beta) cDNAs from the adrenal glands of Dahl's salt-sensitive hypertensive (DS) and salt-resistant normotensive (DR) rats was performed using a combined technique of the first strand cDNA synthesis by reverse transcriptase followed by polymerase chain reaction. The cDNA sequence of P450(11 beta)-DS was identical to that of wild type P450(11 beta). In contrast, the clone obtained from the DR rat contained six nucleotide substitutions causing five amino acid alterations (Arg-127-->Cys, Val-351-->Ala, Val-381-->Leu, Ile-384-->Leu, and Val-443-->Met). When the two cDNAs were expressed in COS-7 cells and steroid conversion rates of the transformed cells were determined, a ratio of 18-hydroxylation to 11 beta-hydroxylation of 11-deoxycorticosterone by P450(11 beta)-DS-expressed cells was 0.58, whereas that by P450(11 beta)-DR-expressed cells was 0.23. Plasma levels of 18-hydroxy-11-deoxycorticosterone and corticosterone (the 11 beta-hydroxylation product of 11-deoxycorticosterone) in DS and DR rats well reflected the steroidogenic activities of the two P450s. These results suggest that the characteristic plasma steroid level of the DR rat is caused by the mutations in P450(11 beta) gene and may act to maintain the normotensive blood pressure in this rat strain during sodium loading.

Recent advances in molecular biology have allowed the study of the candidate genes for essential hypertension. To identify the genes responsible for basal blood pressure in the spontaneously hypertensive rat strain, the rat model of genetic hypertension, we performed a cosegregation analysis between the genotype and blood pressure in a set of male F2 progeny obtained from SHR and Wistar-Kyoto rats, a reference normotensive strain. Our investigation revealed that a locus on the chromosome 4 cosegregates with the blood pressure in SHR, especially at neuropeptide Y locus. The degree of cosegregation with all values of blood pressure without sodium loading was moderate but consistent. We propose that neuropeptide Y locus on chromosome 4 is a new candidate for the hypertensive effect in original SHR.

An association study of the insertion/deletion (I/D) polymorphism located in intron 16 of the ACE gene with essential hypertension in the Japanese population was performed. The 287 bp I/D polymorphism was detected by polymerase chain reaction. Derived allele frequencies for insertion and deletion were not significantly different between 133 hypertensive and 104 normotensive subjects. A significant relationship between I/D polymorphism and plasma ACE activity was observed in the normotensive group, but not in hypertensives. These results suggest that I/D polymorphism of the gene is not implicated in Japanese hypertensive subjects, and that studies involving various ethnic groups are important.