We carried out an association (case-control) study of five candidate genes—G-protein β₃ subunit gene variant; methylene tetrahydrofolate reductase (MTHFR); angiotensin converting enzyme (ACE) gene; and paraoxonase 1 and 2 (PON 1 and 2) genes—in a United Arab Emirati population. The aim was to establish a possible relationship between these five candidate genes and clinical left ventricular hypertrophy (LVH) in a genetically homogenous group. DNA samples were collected from 213 unrelated Nationals who were further segregated into 98 subjects with LVH (78 hypertensives and 20 normotensives) and 115 (23 hypertensives and 92 normotensives) age- and sex-matched controls who did not present with LVH. Of the five candidate gene markers studied, no significant differences in the genotype distribution of the MTHFR, PON 1 and 2 or ACE markers were found between the LVH and non-LVH groups. However, a possible association was found between the β₃ G-protein C825T marker and LVH. In conclusion, our results suggest an association between LVH and the C825T allele of the G-protein β₃ subunit gene. (Hypertens Res 2001; 24: 635-639)

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The object of this study is to evaluate the long-term effects of olmesartan on hypertension and the renin-angiotensin-aldosterone system in hypertensive patients. This study evaluated 26 hypertensive male and female outpatients, 38-69 years of age, with a systolic blood pressure ≥160 mmHg and/or a diastolic blood pressure ≥95 mmHg. Oral doses of 5 to 40 mg olmesartan were administered once daily. Blood pressure and renin-angiotensin-aldosterone parameters (plasma renin activity and plasma angiotensin I, II, and aldosterone concentrations) were evaluated at 12-16 weeks, 6 months, and 1 year after the start of olmesartan administration. Systolic and diastolic blood pressures were significantly decreased following the administration of olmesartan. The observed decreases in systolic and diastolic blood pressures after 1 year of treatment were 28.8±2.1 mmHg and 15.8±1.3 mmHg, respectively. On change was observed in the pulse rate. The plasma renin activity increased significantly from a baseline premedication mean of 1.26±0.31 ng/ml/h to a mean of 2.58±0.74 ng/ml/h and 2.87±0.72 ng/ml/h after 6 months and 1 year of treatment, respectively. Angiotensin II levels decreased significantly from a baseline of 20.4±3.2 pg/ml to a mean of 8.6±2.1 pg/ml and 6.8±1.8 pg/ml after 6 months and 1 year of treatment, respectively. The plasma aldosterone level also decreased significantly after 6 months of treatment. In hypertensive patients, the long-term administration of olmesartan, a novel AT₁ receptor antagonist, decreased both blood pressure and plasma angiotensin II levels. (Hypertens Res 2001; 24: 641-646)

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We investigate the effectiveness of a community-based lifestyle-modification program for reducing blood pressure and other cardiovascular risk factors in sedentary Japanese middle-aged women. Among an initial cohort of 210 middle-aged sedentary women, 195 subjects completed a community-based 12-week lifestyle-modification program for reducing cardiovascular risk factors. Blood pressure, body weight and the serum lipid profile were measured both at baseline and at the end of the 12-week lifestyle-modification program. The program consisted of mild aerobic exercise and a mild hypocaloric diet. After the 12-week program, both systolic and diastolic blood pressure were significantly reduced, especially in subjects who were hypertensive at baseline. Desirable changes in body weight and the serum lipid profile were also found after the 12-week program. Multiple linear regression analysis revealed that, in obese subjects, the decrease in systolic blood pressure was correlated with both the initial systolic blood pressure and the change in estimated maximum oxygen consumption. In addition, the decrease in diastolic blood pressure was correlated with the initial diastolic blood pressure and the change in body weight. On the other hand, in non-obese subjects, the decrease in blood pressure was correlated with the initial blood pressure and the change in salt intake. A community-based lifestyle-modification program that consisted of mild aerobic exercise and a mild hypocaloric diet was considered to be practically effective for reducing multiple cardiovascular risk factors. Individuals who already have one or more mild cardiovascular risk factors still could be good candidates for a community-based lifestyle-modification program. (Hypertens Res 2001; 24: 647-653)

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Activity of daily living (ADL) and cognitive are indices of physical and psychological activity in elderly subjects. The present study was performed to clarify the relationship among ADL, cognitive function, and ambulatory blood pressure (ABP) in the elderly. Study subjects were 77 females and 22 males (aged 60 to 101 years) with various levels of ADL and cognition, who were in nursing homes or geriatric hospitals. ABP was recorded every 30 min for 24 h by a noninvasive device. Mini-mental state examination (MMSE) and Barthel index measurement were used to evaluate congnitive function and ADL, respectively. Both the MMSE and Barthel index values showed a significant positive correlation with daytime ABP but not with nighttime ABP. The dip in nighttime BP correlated negatively with age, and positively with MMSE and Barthel index. In the multiple regression analysis, age and Barthel index values remained significant determinants of the dip in nighttime BP. Presence of stroke and MMSE became significant when the Barthel index values were removed from the analyses. When subjects were classified by tertiles of MMSE or Barthel index, subjects in the lowest MMSE group and those in the lowest Barthel index group had both lower daytime ABP and smaller nighttime BP dip than those of the other groups. A low BP level during the daytime was associated with altered diurnal variation of BP in elderly subjects with greater age, impaired cognitive function, and/or decreased ADL. ADL had a greater influence on diurnal BP variation than did cognitive function. (Hypertens Res 2001; 24: 655-661)

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We studied the association of endothelin (ET)-1 with carotid atherosclerosis and asymptomatic cerebrovascular lesions in patients with essential hypertension. Neurologically normal patients with essential hypertension (n=293; 138 male, 155 female; mean age, 65 years) and age-matched control subjects (n=242) were studied with B-mode ultrasonography of the common and internal carotid arteries and magnetic resonance imaging of the brain. Plasma ET-1 was measured by enzyme immunoassay. Hypertensive patients were divided into groups with carotid plaques and low ET-1 concentrations (<0.75 pg/ml; PL group); carotid plaques and mid-range ET-1 (0.75 to 1.55 pg/ml; PM group); carotid plaques and high ET-1 (≥1.55 pg/ml; PH group); no plaques and low ET-1 (NPL); no plaques and mid-range ET-1 (NPM); and no plaques and high ET-1 (NPH). Overall, ET-1 concentrations were significantly higher in patients than in control subjects. Carotid plaque prevalence was significantly related to ET-1 in hypertensive patients. ET-1 showed a significant positive relationship with the number of asymptomatic lacunar infarcts of the brain in hypertensive patients with carotid plaques (ρ=0.48, p<0.001). No significant relationship was seen between ET-1 and periventricular hyperintensity scores in patients with plaques. ET-1 did not show a relationship to either brain lesion type in patients without carotid plaques. Thus, ET-1 may foster asymptomatic lacunar cerebral infarcts by promoting carotid atherosclerosis in patients with essential hypertension. (Hypertens Res 2001; 24: 663-670)

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The relationship between blood pressure (BP) and cardiovascular morbidity has been appreciated for many years. Casual BP may not be repressentative of the pressure at other times. It is recognized that BP during exercise may be a more accurate predictor than casual BP. There is, however, little information about the effects of antihypertensive drugs on the BP during exercise. This study was designed to investigate the effects of various antihypertensive agents on BP during exercise. Sixty-four patients (age, 49±10 years) with untreated essential hypertension (WHO I, II) were studied during a supine ergometric exercise regimen. A graded exercise test was started at a workload of 50 W, and the load was increased by 25 W every 3 min. The hemodynamic responses to exercise were evaluated by changes in systolic and diastolic BP (SBP, DBP) and heart rate (HR). Plasma norepinephrine (NE) levels were measured at rest and during submaximal exercise, and before and after 4 weeks of treatment with metoprolol (METO), doxazosin (DOXA), trichlormethiazide (TCTZ), nifedipine (NIFE), amlodipine (AMLO) and temocapril (TEMO) between left ventricular mass index (LVMI) and BP values at rest, during exercise, and during the recovery period after exercise were assessed by multiple reguression analysis. The stepwise selection (forward conditional) method showed that LVMI was significantly associated with SBP during submaximal exercise and during the recovery period. All antihypertensive treatments decreased SBP and DBP (p<0.01) at rest. METO, AMLO and TEMO significantly lowered SBP (p<0.05) during exercise, whereas DOXA, TCTZ and NIFE induced no change in SBP. The exercise-induced increase of plasma NE was further enhanced by METO and NIFE but not by AMLO, DOXA, or TCTZ, and it was significantly suppressed by TEMO (p<0.01). There results suggest that BP during exercise is more highly associated with the progression of left ventricular hypertrophy (LVH) than is casual BP. Because antihypertensive agents differ in their effects on exercise hemodynamics, we recommend that hemodynamic factors during exercise be considered when selecting the optimal antihypertensive medication for highly active patients. (Hypertens Res 2001; 24: 671-678)

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The clinical significance of N-type calcium channel blockade has not been fully examined. We here compared the effects of the N-type calcium channel blockers cilnidipine and amlodipine on the sympathetic nervous system and platelet function in hypertension under resting and stressed conditions. Thirty-two patients with hypertension (58±9 years) received cilnidipine or amlodipine for 4 weeks in this crossover study. On day 28 of each treatment, plasma levels of epinephrine (EP), norepinephrine (NEP), and β-thromboglobulin (BTG), and EC₅₀ of ADP- induced platelet aggregation (ADPEC₅₀) were determined at rest and after a cold pressor test. On day 29, the group receiving cilnidipine was switched to amlodipine treatment, and vice versa. At rest, the blood pressure, heart rates, EP, NEP, ADPEC₅₀, and BTG, were similar in both treatments. After the cold pressor test, increases in EP (35±17 to 44±25 pg/ml; p<0.05) and BTG (40±13 to 49±22 ng/ml; p<0.01) and a decrease in ADPEC₅₀ (32±26 to 27±24 μmol; p<0.05) were observed in the amlodipine treatment, but not in the cilnidipine treatment. In addition, the increase in NEP was significantly greater (p<0.05) in the amlodipine (276±78 to 318±87 pg/ml; p<0.01) than in the cilnidipine treatment (273±88 to 291±100 pg/ml; p<0.05). Cilnidipine more highly attenuates the activation of platelet function in response to cold pressor stress then does amlodipine. Attenuated activation of the sympathetic nervous system via N-type calcium channel blockade may contribute to this phenomenon. (Hypertens Res 2001; 24: 679-684)

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Few tools for risk assessment of coronary heart disease (CHD) have yet been made availabe in Japan. This study aims to examine the validity of the updated Framingham risk score as applied to a Japanese male population. Using the annual health examination database of a Japanese company, we followed-up 5, 611 male subjects, aged 30 to 59 years, who had initially recorded neither history of cardiovascular disease nor electrocardiographical ischemic changes, in order to observe the occurrence of CHD over a period of 5 to 7 years. The total score calculated by the Framingham risk score sheet (the Framingham point score) was used as an indicator of CHD risk for the subject individually. The mean of the Framingham point score for 80 CHD cases was significantly higher than that for 5, 531 non-CHD cases. The incidence of CHD gradually increased with the Framingham point score. In the receiver operating characteristic analysis, the area under the curve reached 0.71. At 6 points, the curve came closest to the upper left-hand corner, with a specificity of 0.74 and sensitivity of 0.59. On the other hand, multivariable-adjusted relative risks associated with old age, high blood pressure, low HDL cholesterol and smoking in the Japanese male population were different from those in the Framingham population. Despite the low incidence of CHD, the updated Framingham risk score could provide a reasonable rank ordering of CHD risk and could identify Japanese men (and possible other individuals) at high risk for CHD with considerable accuracy. However, further study of Japanese populations may be required to reappraise several coefficients of risk factor in the risk scoring model. (Hypertens Res 2001; 24: 685-689)

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A high level of serum creatinine (S-Cr) is a predictor of end-stage renal disease (ESRD), but only a few studies have investigated the prevalence of high S-Cr and its correlates in a large population. We analyzed the data collected from 6,403 subjects (4,222 men and 2,181 women) who participated in the Okinawa General Health Maintenance Association (OGHMA) screening both at 1997 and 1999. The computer-saved data included sex, age, blood chemistries, blood pressure, medical histories, and lifestyles. Multivariate Cox proportional hazard analyses were performed to identify the correlates of developing high S-Cr levels: ≥1.4 mg/dl in men and ≥1.2 mg/dl in women. The prevalence of high S-Cr was 3.0% (N=193), which was 4.1% in men (N=175) and 0.8% in women (N=18), and increased with age in both sexes at the 1997 screening. Among those who showed normal levels of S-Cr in 1997 (N=6,210), 241 subjects (223 men and 18 women) developed high S-Cr. The 2-year cumulative incidence of high S-Cr was 5.5% in men and 0.8% in women. Other than sex, serum uric acid was the most significant correlate for developing high S-Cr. The adjusted relative risk (95% confidence interval) of those with serum uric acid 8.0 mg/dl and over was 2.91 (1.79-4.75) in men and 10.39 (1.91-56.62) in women when compared to those with serum uric acid less than 5.0 mg/dl. Prevalence of high levels of S-Cr was relatively high in men. Other than gender, serum uric acid was a significant positive correlate of developing high S-Cr in this sample of the Japanese population. (Hypertens Res 2001; 24: 691-697)

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The aim of this study was to examine whether nitric oxide (NO) buffers the renal medullary vasoconstriction induced by a prostaglandins (PG) synthesis inhibitor. Daily blood pressure measurements were made with implanted catheters and changes in cortical blood flow (CBF) and medullary blood flow (MBF) were determined by implanted optical fibers and laser-Doppler flow measurement techniques in conscious rats. Sodium and water balance were also determined. Infusion of meclofenamate, a nonisozyme-specific cyclooxygenase (COX) inhibitor, at 5μg/kg/min over 4 consecutive days (n=12 rats) elicited a transitory increase (p<0.05) in mean arterial pressure (MAP) and a transitory decrease (p<0.05) in MBF and sodium excretion without altering CBF. In contrast, the simultaneous infusion of meclofenamate and N^G-nitro-L-arginine methyl ester (L-NAME, 0.8μg/kg/min), a NO synthesis inhibitor, over 4 consecutive days (n=12) produced a continuous increase (p<0.01) in MAP and a continuous decrease (p<0.05) in MBF and sodium excretion without altering CBF. The results of this study suggest that the renal medullary vasoconstrictor effects and sodium retention induced by meclofenamate are enhanced by a subpressor dose of L-NAME, and that NO may buffer the renal medullary vasoconstriction induced by the blockade of PG synthesis in conscious rats. (Hypertens Res 2001; 24: 699-704)

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Targeted disruption of the klotho gene induces multiple phenotypes characteristic of human aging, including arteriosclerosis, pulmonary emphysema and osteoporosis. Moreover, we previously observed that insufficient klotho expression in mice leads to endothelial dysfunction. In the present study, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit hypertension, obesity, severe hyperglycemia and hypertriglyceridemia, and are thus considered an animal model of atherogenic disease, to test the effects of oral administration of troglitazone (200 mg/kg) on renal klotho mRNA expression and endothelial function. Systolic blood pressure, body weight, plasma glucose and triglyceride levels were all significantly higher in 30-week-old OLETF rats than in controls (LETO; Long-Evans Tokushima Otsuka) (p<0.05, n=7). In addition, endothelium-dependent relaxation of the aorta in response to 10^-5 M acetylcholine was significantly attenuated in OLETF rats (p<0.05, n=7), as was renal expression of klotho mRNA. Administration of troglitazone for 10 weeks significantly reduced systolic blood pressure, plasma glucose and triglyceride levels in OLETF rats, while augmenting endothelium-dependent aortic relaxation and renal klotho mRNA expression. These findings suggest that troglitazone protects the vascular endothelium against damage caused by the presence of multiple atherogenic factors. (Hypertens Res 2001; 24: 705-709)

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The purpose of this study was to determine whether a high NaCl intake impairs endothelium-dependent and -independent vasodilation of forearm circulation in salt sensitive (SS) patients with essential hypertension. We evaluated the effects of intra-arterial acetylcholine (ACh) and isosorbide dinitrate (ISDN) on forearm hemodynamics in 29 patients with essential hypertension, while consuming a low NaCl (50 mmol/d) or high NaCl (340 mmol/d) diet for 1 week. The forearm blood flow (FBF) was measured by strain-gauge plethysmography. Patients were classified as SS (n=12) or salt resistant (SR; n=17) based on salt-induced changes in blood pressures. The FBF responses of ACh and ISDN were similar in the SS and SR patients while on either NaCl diet, and was not altered by salt loading (ACh, SS: low NaCl 22.8±4.3 vs. high NaCl 21.1±3.6 ml/min per 100 ml, SR: low NaCl 22.5±4.0 vs. high NaCl 23.3±4.1 ml/min per 100 ml; ISDN, SS: low NaCl 13.9±2.1 vs. high NaCl 14.1±2.2 ml/min per 100 ml, SR: low NaCl 13.8±2.3 vs. high NaCl 14.0±2.2 ml/min per 100 ml). There were no significant differences in the vascular responses to ACh and ISDN in the presence of N^G-monomethyl-L-arginine, a nitric oxide synthase inhibitor, in either group for either NaCl diet. These findings suggest that forearm resistance artery endothelial function may not be influenced by salt loading in either SS patients which finding may play a role in determining salt sensitivity in patients with essential hypertension or SR patients. (Hypertens Res 2001; 24: 711-716)

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There is considerable evidence to indicate that humoral factors play an important role in the development of left ventricular hypertrophy. Cardiotrophin-1 (CT-1) is a cytokine that has been shown to induce cardiac hypertrophy in a dose-dependent manner. The aim of the present study was to investigate the acute effect of CT-1 on hemodynamic parameters in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) and to study the relationship between the plasma concentration of CT-1 and its hemodynamic effect. Ten-week-old SHR and age-matched WKY were used. Blood pressure (BP), heart rate (HR) and plasma concentration of CT-1 were measured both before and for 60 min after intravenous bolus injection of human CT-1 (10 μg/kg). CT-1 injection significantly decreased BP and significantly increased HR in SHR and WKY. There were significant differences in BP and HR between the two groups at all time points after injection. The lowest BP, highest HR and maximal plasma concentrations of CT-1 were observed in both groups within 10 min after injection. However, after converting the values into the percentage change from their respective baselines, there were no significant differences between the two groups in BP or HR at any time point. There was also no significant difference between the two groups at any time point in the plasma concentration of CT-1. This study indicates that CT-1 decreases BP and increases HR in both SHR and WKY. The most obvious change occurred within 10 min after injection. However, there was no significant difference in the hypotensive effect of CT-1 on 10-week-old SHR and WKY. (Hypertens Res 2001; 24: 717-721)

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A 55-year-old woman was referred to our institution for evaluation of elevated plasma creatine phosphokinase, hypokalemia and hypertension. Her chief complaints were muscle weakness and polyuria. A left adrenal mass, 4 cm in diameter, was noted on computed tomography. Hormonal assessment demonstrated markedly elevated plasma aldosterone concentration, markedly low plasma renin activity, an abnormal diurnal variation in serum cortisol levels, suppressed baseline plasma adrenocorticotrophic hormone, and non-suppression of serum cortisol by dexamethasone suppression test. She showed no symptoms or signs suggestive of Cushing’s syndrome. Adrenal scintigraphy with ¹³¹I-6-β-iodomethyl-norcholesterol showed uptake on the left adrenal and inhibition of the contralateral adrenal gland. She was diagnosed with combined primary aldosteronism and preclinical Cushing’s syndrome. Cases of combined primary aldosteronism and preclinical Cushing’s syndrome are extremely rare. In patients with large aldosterone-producing adenoma, contralateral adrenal insufficiency should be anticipated after the removal of the tumor. (Hypertens Res 2001; 24: 723-726)

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Ouabain has recently been identified as an endogenous Na⁺-K⁺ pump inhibitor having a close association with hypertension. However, some patients with hypertention do not show high levels of endogenous ouabain (EO), and patients with high EO levels do not necessarily suffer from hypertention. It is believed that the Na⁺-K⁺-ATPase activity in essential hypertension does not undergo homogenous change. The present study was designed, therefore, to investigate the expression and the significance of the Na⁺-K⁺-ATPase α-subunit isoforms in kidney tissue in ouabain-hypertensive rats. Ouabain was administered chronically to establish a model of ouabain-hypertensive rats. Biochemical analysis, cytobiology and sABC immunohistochemistry were they used to assay for expression of Na⁺-K⁺-ATPase α-subunit isoforms in kidney tissue. After the first week of receiving ouabain, 65% (n=13) of rats had hypertension. After the second week, the blood pressure of these 13 hypertensive rats was increased significantly compared to the baseline and control levels (p<0.05). The plasma renin activity was normal, and angiotensin II and aldosterone levels were increased significantly in these rats (p<0.05). But in the other 35% (n=7) of rats of the experimental group, there was no apparent increase in blood pressure after receiving ouabain. The plasma ouabain level in the non-hypertensive subgroup was significantly higher than that in the hypertensive subgroup, but the ⁸⁶Rb intake and the number of ³H-ouabain binding sites did not decrease. The Na⁺-K⁺-ATPase activity showed non-homogeneous changes. In hypertensive rats, the expression levels of ouabain paralleled the degree of hypertension (r=0.88, p<0.05). The positive granules were mainly scattered in the cytoblastoma of the reticular zone of adrenal cortex. There were thus different levels of expression of Na⁺-K⁺-ATPase α-subunit isoforms in this model. In the hypertension subgroup the α₁ was most strongly expressed, followed by the α₂ and α₃ isoforms. But in the non-hypertensive subgroup the order was α₃>α₂>α₁. The positive granular was mainly scattered in the convoluted tubules of the kidney. These results suggest that the high level of ouabain and the change of the Na⁺-K⁺-ATPase α-subunit isoforms may play a critical role in hypertension. (Hypertens Res 2001; 24: 729-734)

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The preventive effects of sesamin, a lignan from sesame oil, and vitamin E on hypertension and thrombosis were examined using stroke-prone spontaneously hypertensive rats (SHRSP). At 5 weeks of age the animals were separated into four groups: (i) a control group; (ii) a vitamin E group, which was given a 1,000 mg α-tocopherol/kg diet; (iii) a sesamin group, given a 1,000 mg sesamin/kg diet; and (iv) a vitamin E plus sesamin group, given a 1,000 mg α-tocopherol plus 1,000 mg sesamin/kg diet for 5 weeks from 5 to 10 weeks of age. Resting blood pressure was measured by the tail-cuff method once weekly. A closed cranial window was created and platelet-rich thrombi were induced in vivo using a helium-neon laser technique. The number of laser pulses required for formation of an occlusive thrombus was used as an index of thrombotic tendency. In control rats, systolic blood pressure and the amount of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) became significantly elevated with age. However, the elevation in blood pressure and 8-OHdG were significantly suppressed in rats administrated vitamin E, sesamin, or vitamin E plus sesamin. At 10 weeks, the number of laser pulses required to induce an occlusive thrombus in arterioles of the control group was significantly lower than in the other groups (p<0.05). These results indicate that chronic ingestion of vitamin E and sesamin attenuated each of elevation in blood pressure, oxidative stress and thrombotic tendency, suggesting that these treatments might be beneficial in the prevention of hypertension and stroke. (Hypertens Res 2001; 24: 735-742)

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