Michio Ueno

Long-Term Compliance with Salt Restriction in Japanese Hypertensive Patients

The purpose of the present study was to investigate the long-term compliance with salt restriction in Japanese hypertensive patients. Subjects included 389 patients, 230 women and 159 men, mean age 58±11 years, who underwent successful 24-h home urine collection more than three times over an interval of a year. Urinary salt, potassium, and creatinine were measured. Additionally, family history, habitual alcohol intake, smoking habit, physical activities, and job status were assessed by use of a questionnaire. During the follow-up period (average 3.5 years), participants underwent urine collection 4.6 times in average. Urinary salt excretion at the last visit was significantly lower than that at the first visit (8.7±3.4 vs. 9.6±4.1 g/day; p<0.01). Urinary potassium excretion also decreased significantly during this period (from 2.0±0.7 to 1.9±0.7 g/day; p<0.05). Among the mean 4.6 urine collections, 45.2% (men 34.6%, women 52.6%) of the patients successfully achieved <6 g (100 mmol of sodium)/day of salt excretion on at least one occasion. The rate of achievement of averaged urinary salt excretion <6 g/day dropped to 10.3% (men 4.4%, women 14.3%). Only 2.3% (men 0.6%, women 3.5%) of the patients achieved <6 g/day on all occasions. There were no significant differences in age, habitual alcohol intake, smoking habit, physical activities, or job status between patients who complied with the salt-restricted diet and those who did not. Results suggest that long-term compliance with salt restriction is poor in Japanese hypertensive patients. Since no specifically defining characteristics were found in the compliant patients, repeated measurements of urinary salt excretion seem to be important to encourage salt restriction.

Prevalence and Lifestyle Characteristics of Hypertensive Patients with Metabolic Syndrome Followed at an Outpatient Clinic in Fukuoka, Japan

A new guideline on metabolic syndrome (MS) in Japanese was introduced in 2005. The purpose of this study was to evaluate the prevalence and lifestyle characteristics of Japanese hypertensive patients with MS. Subjects were 290 patients (mean age: 64±11 years) who had been followed at our hospital. The waist circumference (WC) and body mass index (BMI) were assessed. Subjects who had BMI ≥25 kg/m2 were defined as having BMI obesity, while abdominal obesity was defined as a WC ≥85 cm in men and ≥90 cm in women, respectively. Since all patients had hypertension, the definition of MS was made when the patient had abdominal obesity plus either dyslipidemia or glucose intolerance, or both. Among the subjects, 230 patients underwent 24-h home urine collection to measure urinary salt and potassium excretions. Dietary habits were also assessed by use of a questionnaire. Mean values of BMI and WC were 24.2±3.4 kg/m2 and 87.1±9.6 cm, respectively. Among the total subject group, 39% patients were classified as having BMI obesity, 49% as having abdominal obesity, and 27% as having MS. BMI was significantly correlated with WC both in men (r=0.86; p<0.01) and in women (r=0.79; p<0.01). More men than women belonged to the BMI obesity (46% vs. 33%, p<0.05), abdominal obesity (63% vs. 39%, p<0.01) and MS (39% vs. 18%, p<0.01) groups. There were no significant differences in blood pressure between patients with and without MS, while patients with MS needed a greater number of antihypertensive drugs than those without MS. Mean urinary salt and potassium excretions were 8.9±3.8 g/day and 1.9±0.7 g/day, respectively. Urinary salt excretion of <6 g (100 mmol of sodium)/day was achieved in 20% of the subjects. Urinary salt excretion in the patients with MS was significantly higher than that in the patients without (10.1±4.2 vs. 8.5±3.6 g/day; p<0.01). Only 16% of the patients with MS achieved salt restriction (<6 g/day). The patients with MS had a significantly greater the chance to eat out than the patients without MS. They were also less aware of the need to increase their vegetable consumption. The results suggested that MS is prevalent in Japanese hypertensive patients. Patients with MS showed higher urinary salt excretion and needed more antihypertensive drugs to manage their blood pressure. Dietary counseling focusing not only on sodium restriction but also on the need to increase fruit and vegetable consumption seems to be important.

Circadian Variations of Urinary Dopamine, Norepinephrine, Epinephrine and Sodium in Normotensive and Hypertensive Subjects

Under standardized conditions, we determined circadian urinary excretion of sodium (Na) and free dopamine (DA), norepinephrine (NE) and epinephrine (E) in 20 normotensive, 20 borderline hypertensive and 10 mild hypertensive middle-aged men. The 24-hour excretions of water, Na, DA, NE and E were comparable between the normotensives and the hypertensives. In the total study population, these parameters showed significant time-related changes: high excretion during the daytime and low excretion in the night. The circadian variations of urinary DA, NE and E were similar among the 3 groups. The circadian curve of urinary DA was similar to those of Na and water excretion. In the total study population, 24-hour water and Na excretion correlated positively with urinary DA, but not with NE or E. These results suggest that endogenous DA may play a role in the circadian variation of water and sodium metabolism. The circadian excretion of urinary catecholamines may not be altered in middle-aged subjects with borderline or mild hypertension.

Antihypertensive effect of E-643, a new alpha-adrenergic blocking agent

SummaryTo determine whether E-643, a new α-blocking agent, would reduce the blood pressure, regardless of the posture, a 1 mg dose was given 3 times daily for 7 consecutive days, to 8 male and 7 female inpatients, aged 37–73 years, with essential hypertension. Blood pressure and pulse rate were measured daily in the supine, sitting and standing positions. Before and after the treatment with E-643, plasma levels of noradrenaline, adrenaline, dopamine-β-hydroxylase, renin and aldosterone were determined, samples being obtained with the subjects recumbent and after standing upright for 60 min. A significant reduction in the systolic and diastolic blood pressures was evident in the supine (172±31/100±12 → 151±28/89±14 mmHg), sitting (158±22/101±11 → 138±28/89±15 mmHg) and standing (153±32/103±21 → 129±31/89±20 mmHg) positions. The reduction in blood pressure remained unchanged throughout the period of administration of E-643. Pulse rate was not affected when the subjects were supine (67±10 → 69±10 beats/min), but was increased in the sitting (68±10 → 73±9 beats/min) and standing (73±10 → 81±11 beats/min) positions. The increased pulse rate tended to decline during continued administration of E-643. Treatment with E-643 produced no significant change in plasma levels of adrenaline, noradrenaline, dopamine-β-hydroxylase, renin and aldosterone. The antihypertensive effect of treatment was more prominent in the patients with higher levels of plasma catecholamines and dopamine-β-hydroxylase, and was less prominent in those with higher plasma renin and aldosterone. Two patients had temporary bouts of dizziness and visual disturbances, but there were no subjective complaints during treatment.

Differences and similarities among circadian characteristics of plasma renin activity in healthy young women in Japan and the United States

A circadian rhythm of plasma activity (PRA) was demonstrated for both Japanese and North American women, the latter mostly Caucasians of mixed ethnic origin. The results were based on blood samples withdrawn at 4-hour intervals during a 24-hour span (in March 1978) from 20 subjects from Fukuoka (average age 20.4 +/- 0.1 years) and 16 subjects from Minneapolis (average age 20.2 +/- 0.4 years). The rhythms in the two populations showed similarities in some characteristics and differences in others. The timing of high values, i.e., of acrophases, objectively assessed by curve-fitting (and of corresponding 95 per cent confidence limits) was at 07(36) (05(00), 10(16) and 06(32) (03(00), 10(00) for Japan and USA, respectively. As objective measures of the extent of predictable rhythmic change mean amplitudes, in nanograms per milliliter per hour (ng/ml/hour), were similar (0.31 and 0.32); a statistically significant difference (P less than 0.05) was found in mean amplitudes expressed as percentage of the rhythm-adjusted average. Mean rhythm-adjusted average values (mesors) were lower in women from Japan than in those from the United States: (1.64 +/- 0.14 and 2.39 +/- 0.23 ng/ml/hour, respectively; P less than 0.01). A statistically significant difference in dietary salt, indicated by differences between the Japanese and North American women in the urinary excretion of sodium and chloride (P less than 0.05), almost certainly contributed to these results.

Genome-wide response to antihypertensive medication using home blood pressure measurements: a pilot study nested within the HOMED-BP study

BACKGROUND Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). METHODS We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. RESULTS SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. CONCLUSION Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension.

Antiproteinuric effect of an N-type calcium channel blocker, cilnidipine

The objective of the present study was to determine antiproteinuric effect of an N-type calcium channel blocker—cilnidipine. Subjects were 43 essential or renal hypertensive subjects who had been taking calcium channel blockers other than cilnidipine for at least 6 months. All patients had proteinuria greater than 0.2 g/day in spite of fair blood pressure control (< 150/90 mmHg). Calcium channel blockers in 25 patients (62 ± 3 years) were switched to cilnidipine (cilnidipine group), whereas other 18 patients (58 ± 3 years) continued to take originally prescribed calcium channel blockers (control group). The 24-hr urine collections were done at baseline and after 6 months of the follow-up period. Baseline characteristics including age, blood pressure levels, body mass index and creatinine clearance were similar between cilnidipine and control groups. Urinary protein excretion also was comparable between cilnidipine (0.61 ± 0.10 g/day) and control (0.86 ± 0.17 g/day) groups. Urinary protein significantly decreased after 6 months in cilnidipine group (− 0.21 ± 0.11 g/day, − 36%, p < 0.01), whereas it did not change in control group (+ 0.01 ± 0.15 g/day, 0.4%, ns). There were no significant changes in blood pressure, serum creatinine, creatinine clearance, estimated protein intake, and urinary salt excretion during the follow-up period in either group. The reduction of urinary protein by cilnidipine was evident in essential hypertensives (− 54 ± 9%, n = 18, p < 0.01) but not in renal hypertensives (+ 10 ± 35%, n = 7, ns). Results suggest that cilnidipine has an antiproteinuric effect especially in patients with essential hypertension.

Comparison of withdrawing antihypertensive therapy between diuretics and angiotensin converting enzyme inhibitors in essential hypertensives

One hundred thirteen patients with essential hypertension receiving single or multiple antihypertensive agents were enrolled in the study. All had had mild to severe hypertension before treatment, but their diastolic blood pressure (DBP) at study entry was lower than 90 mm Hg for all measurements. In half of the subjects, non-thiazide diuretics (n = 35) or angiotensin-converting enzyme inhibitors (ACEI, n = 37) were discontinued, and their remaining drugs were maintained throughout the study. The other patients (n = 41) continued all their medications. Forty-one percent of subjects remained normotensive for 12 months after withdrawal of diuretics, and 37% of patients with ACEI discontinuation remained normotensive, although the recurrence of hypertension after withdrawal of ACEI tended to be earlier than its recurrence after withdrawal of diuretics. Serum uric acid and creatinine concentration decreased after diuretic withdrawal, but not after ACEI withdrawal. Diuretic withdrawal resulted in an increase in serum potassium, but ACEI withdrawal induced a decrease in serum potassium. Withdrawal of diuretics or ACEI both significantly reduced plasma renin activity. The present study may be indicative of the ability to withdraw some medications in many patients being treated with multiple antihypertensive agents.

Circadian Characteristics of Urinary Epinephrine and Norepinephrine from Healthy Young Women in Japan and USA

Clinically healthy diurnally active young adult women were studied during the same season (March) at the Universities of Kyushu (Fukuoka City, Japan) and of Minnesota (Minneapolis, U.S.A.), under comparable conditions, except that the habitual diets were not changed. The subjects (20 Japanese and 16 Americans of mixed Caucasian background) were studied over a single 24-hr span. Urine was collected at 4-hr intervals. A circadian rhythm in total urinary norepinephrine excretion showed similar characteristics in Japanese and Americans. In epinephrine excretion, the Japanese women showed a statistically significantly higher amplitude with higher peak values, but no statistically significant difference in the rhythm-adjusted mean. This intergroup difference is strictly time dependent; it does not come to the fore in urine samples covering the nocturnal rest span of the subjects.

Is single oral administration of captopril beneficial in screening for primary aldosteronism

Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 19 cases with primary aldosteronism (PA) and in 72 with essential hypertension (EHT) to differentiate the two disorders during the following conditions on normal salt diet: after overnight recumbency (basal state) and 2 hours after oral administration of 25 mg of captopril. Screening criteria were determined so that all PA patients were diagnosed as positive, and their specificities were compared with those of other conventional screening methods for PA. After captopril administration, the specificity of a criterion based on a combination of PAC and PAC/PRA ratio was 93% and positive predictive value was 79%. This criterion was superior to blood pressure response to angiotension II analog infusion, PRA on salt depletion, and to PAC on salt loading. However, higher specificity (97%) and positive predictive value (90%) were obtained from a criterion based on a combination of basal PAC and PAC/PRA ratio. Therefore, the use of a combination criterion based on PAC and PAC/PRA ratio at basal state rather than after captopril administration may give a satisfactory result in the screening for PA.