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Purpose: We examined the effect of the angiotensin II receptor antagonist (ARB), irbesartan (Irb), on urinary markers in hypertensive patients., Subjects and Methods: We evaluated 87 patients in a 12-month prospective study: Group 1) 33 patients who were newly administered Irb (100 mg); Group 2) 33 patients who were switched to Irb ; and Group 3) 21 patients who did not undergo change to pre-existing Irb administration. Height, weight, systolic and diastolic blood pressure, clinical parameters, urine protein : creatinine ratio (UPC), and urinary markers (liver-type fatty acid binding protein (L-FABP), N-acetyl-β-d-glucosaminidase, α1-microglobulin, and β2-microglobulin) were measured at the baseline and at 12, 24, and 48 weeks. We examined changes in the clinical parameters, UPC, and urinary markers from the baseline., Results: A tendency toward hypotension was observed in all groups (group newly administered Irb, group switched to Irb, and group without changes to Irb), but the difference was not statistically significant. Urinary L-FABP concentration (μg/g x Cr) decreased from 13.2 --> 8.9 and13.2 --> 10.2 at 24 and 48 weeks, respectively, after administration (p < 0.01) in the group newly administered Irb, from 19.5 --> 10.1 at 48 weeks after administration (p < 0.01) in the switched group, and from 9.6 --> 8.3, 8.1, and 6.2 (p < 0.01) in the group without changes to Irb. Changes in the Irb-administered groups were readily apparent. UPC decreased in the Irb-administered groups (p < 0.05), but there were no significant differences in the other urinary markers. Changes in urinary L-FABP and UPC were positively correlated in all cases of the Irb-administered groups (r = 0.25-0.57, p < 0.05), but were not positively correlated in the group without changes to Irb administration. The change in UPC was positively correlated with changes in systolic and diastolic blood pressure in all cases (r = 0.23-0.57, p < 0.05)., Conclusion: It was concluded that the urinary L-FABP level, blood pressure, and UPC of hypertensive patients should be managed in daily practice using an ARB, including Irb.

Purpose: To examine changes in urinary excretion of sodium, potassium and sodium/potassium ratio in a community-based health education program on salt reduction., Subjects and Methods: The surveyed community was Kyowa town (census population in 1985 = 16,792) where we have conducted a community-based blood pressure control program since 1981 and health education on reduction of salt intake since 1983 for primary prevention of hypertension. A 24-hour urine collection was conducted for systematically selected samples of the participants aged 40-69 in cardiovascular risk surveys in 1982-86 (early period) and in 1990-94 (later period) to estimate changes in urine excretion of sodium, potassium, and sodium/potassium ratio., Results: A 24-hour urine collection was available for 565 persons (410 men and 155 women) in 1982-86 and 1,461 persons (571 men and 890 women) in 1990-94. A decline in mean sodium excretion was larger in ages 40-49 than in other age groups, and for ages 40-69 combined, the decline was 0.9-1.1 g per day for men and women. Mean sodium excretion declined to 10 g or less per day for men and women aged 60-69. Mean potassium excretion did not change except for men aged 60-69 with an increase in potassium. Sodium/potassium ratio tended to decline for women aged 40-49, and declined significantly for other sex-age groups. A larger reduction in sodium excretion was seen among persons with a history of hypertension compared to those without it., Conclusions: A significant reduction in urinary excretion of sodium and sodium/potassium ratio was observed in a community-based health education program. Men and women aged 60-69 reached a recommended level of 10 g or less in sodium intake.

The present study aimed to elucidate the role of renal dopaminergic and prostaglandin (PG) systems in renal uric acid metabolism in essential hypertension. Mean arterial pressure (MAP), heart rate (HR), endogenous creatinine clearance (Ccr), serum uric acid (SUA), urinary excretions of uric acid (UUAV) and sodium (UNaV), fractional excretions of uric acid (FEUA) and sodium (FENa), plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured before and after intravenous injection of a dopamine receptor antagonist, metoclopramide (MCP: 8 mg/m2.BSA), or before and after a single oral administration of prostaglandin synthesis inhibitor, indomethacin (IM: 75 mg), in 34 mild-to-moderate essential hypertensives (EHT). MCP injection or acute oral administration of IM caused significant decreases of UNaV and FENa in each group, whereas MAP, HR and SUA did not change in either group. Significant decreases in Ccr, UUAV and FEUA and increases in PRA and PAC were demonstrated by MCP injection, while no significant changes in these parameters were revealed by IM administration. There was a significant positive correlation between delta UUAV and delta Ccr or delta FEUA in both groups. In addition, a close positive correlation between delta UUAV and delta UNaV as well as between delta FEUA and delta FENa was found in the MCP group, but not in the IM group. On the other hand, no significant correlation was observed between delta UUAV and delta PRA or delta PAC in either MCP or IM administration. The decreases of UUAV and FEUA were significantly greater in MCP than in IM administration, despite similar changes in Ccr, UNaV and FENa between the two procedures. These data suggest that the endogenous renal dopaminergic system may contribute to renal uric acid metabolism, which is rather closely related to sodium handling in essential hypertension than the prostaglandin system. Furthermore, the attenuated renal dopaminergic activity may contribute to the elevation of serum uric acid level in patients with essential hypertension.

We all agree to the importance of the salt restriction in the prevention and the treatment of hypertension. But it is not easy to teach the way to reduce salt intake in each person or patient. And we also not confident that how long could they maintain the low salt diet. In this study we investigate following problems, 1) Can the salt intake be reduced in public population? 2) Can blood pressure be lowered by reducing salt intake in mildly hypertensive individuals? 3) If the desired changes are obtained, can they be preserved for a long time? and 4) Are there any difference in the amount of the salt intake between hypertensives and normotensives? One hundred and forty subjects from 23,940 people in whom borderline to mild hypertension was found at group medical examinations in each district, where a total of 29,940 people were examined, were registered to a educational course of new salt-restriction program. Salt intake was estimated from salt measurement in 24-hour urine samples. Educational program was composed of many lectures, sampling party and individualized consultations about dietary problems, using an original dietary questionnaire list. The results were as follows: In short-term (2.5 months) after the initial education, sodium intake reduced from 235.1 +/- 110.8 mmol/day to 161.4 +/- 85.0 mmol/day (p less than 0.001). The systolic and diastolic blood pressure also fell significantly in borderline hypertensives (from 148 +/- 7/87 +/- 5 mmHg to 141 +/- 12/85 +/- 7 mmHg, p less than 0.001) and hypertensives (from 165 +/- 13/99 +/- 8 mmHg to 157 +/- 15/95 +/- 8 mmHg, p less than 0.001) but they did not change in normotensives (from 133 +/- 6/80 +/- 6 mmHg to 131 +/- 9/82 +/- 8 mmHg). In long-term (range from 12 to 36 months) observation, low salt diet (167.6 +/- 72 mmol/day) and a fall in blood pressure were also maintained in borderline (142 +/- 2/85 +/- 7 mmHg, p less than 0.001) to hypertensive population (156 +/- 14/93 +/- 8 mmHg, p less than 0.001), and in the normotensive population, no change in blood pressure was observed (134 +/- 13/82 +/- 9 mmHg). Hypertensives tended to show higher sodium intake than normotensives (206 +/- 101 mmol/day vs. 199.0 +/- 96, p less than 0.005), and also show higher sodium/potassium ratio than normotensives and borderline hypertensives (4.3 +/- 2.3 vs. 3.6 +/- 1.6 and 3.8 +/- 1.8, p less than 0.005).(ABSTRACT TRUNCATED AT 400 WORDS)

A method of radioimmunoassay for urinary aldosterone excretion (AER) using 125I-labeled ligand [ALDOCTK-125KIT] is described. The sensitivity, specificity, reproducibility and accuracy of this method were compared with the 3H-RIA method previously reported. Since the extraction method using ALDOCTK-125KIT was considered to be preferable to the direct method, the former method was applied to the present study. An excellent correlation was found between the values determined by the 3H-RIA method and the extraction method (r = 0.935, p less than 0.001, Y = 0.89X + 0.80, n = 146). The within-assay and the between-assay coefficient of variation was 7.7--15.0% and 9.7--12.2%, respectively. As a clinical application, the circadian variation of AER was investigated in 5 control subjects and groups of essential hypertension (EHT), primary aldosteronism (PA), chronic glomerulonephritis (CGN) and Cushing's syndrome, each of which consisted of 5 patients, all of which had serum creatinine concentrations of less than 1.2 mg/dl. Under a control diet containing 10 g of salt per day, urine was collected in 4-hour pools starting at 8:00 for the ensuing 24 hours, and AER was determined by means of both 3H-RIA and the extraction method. The difference of the values between the peak and the nadir in each subject was statistically significant, and marked and identical circadian variations of AER with the peak and the nadir at the period of 4:00 to 12:00 and 20:00 to 4:00 were observed in the control, EHT, PA and CGN groups. In the Cushing group, however, the circadian variation of AER was different from the other 4 groups: the peak and the nadir of AER occurred at the period of 20:00 to 24:00 and 4:00 to 8:00, respectively. The circadian variation of AER became more obvious in all groups including the Cushing, when each value was expressed in the percentage of the mean. AER under the control diet was 9.38 +/- 2.04 micrograms/day in the control subjects. In PA and CGN, AER was significantly higher, and in the Cushing group, it was significantly lower than that observed in the control. However, no difference was found in AER between the control and EHT. AERs in both 4-hour and 24-hour urine specimens measured by ALDOCTK-125KIT were consistent with those by the 3H-RIA method.

Whether to determine the urinary kallikrein (UKK) levels in the second trimester of pregnancy is valuable in predicting of gestosis, especially of hypertension, was studied using samples of urine obtained from 500 cases of pregnant women without gestosis, 50 pregnant women with gestosis and 50 cases of pregnancy with a variety of complications other than gestosis. The main results obtained were as follows: In normal pregnancy, UKK levels elevated with pregnancy for a peak in the first to the second trimester of pregnancy, tapering off thereafter. The UKK level was significantly lower in 20 pregnant women with gestosis especially in hypertensive type than in pregnant women without gestosis (p less than 0.001). Pregnant women with normal blood pressure who suffered no gestosis and had an extremely low UKK level, accounted for 9.8% of all pregnant women studied. This figure includes a large number of those who were in a high risk group for the onset of gestosis. From these findings, UKK was considered to be useful as one of the factors used in predicting the onset of hypertension in association with gestosis and we are now studying pregnant women in the 20th and 30th week of pregnancy in more detail.

Recently, it has been recognized that 19-hydroxyandrostenedione (19-OH-AD), one of the C19 steroids, acts to amplify the mineralocorticoid activity and to elevate blood pressure. However, there is no detailed report about the pressor mechanism and the effects on several humoral depressor factors, i.e., kallikrein, kinin and prostaglandins etc. Therefore, we studied the differences in the pressor mechanisms and the changes in urinary prostaglandin E (PGE) and kinin excretions among deoxycorticosterone acetate (DOCA)-salt hypertension, 19-OH-AD induced hypertension, and testosterone induced hypertension. In this study, DOCA, 19-OH-AD and testosterone were administered subcutaneously to castrated male rats (Wistar rats, 12 weeks) at a dose of 10 mg/body/week for the first 6 weeks. Then the doses were increased to 30 mg/body/week for the next 5 weeks. These experiments were done in metabolic cages. It was found that 19-OH-AD induced hypertension earlier than DOCA and testosterone. However, 19-OH-AD and testosterone had no effect on the levels of urinary kinin and PGE excretions, while DOCA significantly increased urinary kinin and PGE excretions immediately after the onset of hypertension. Furthermore, DOCA increased the urinary Na/K ratio, while 19-OH-AD and testosterone did not change the ratio. It is suggested that 19-OH-AD might induce the pressor action due to the changes in the vascular reactivity rather than the mineralocorticoid activity.

Several aldosterone metabolites are now known to possess some mineralocorticoid activities. In order to test the hypothesis that these metabolites could contribute to the pathogenesis of hypertension, we studied the aldosterone metabolism in SHR in vitro and in vivo. In vitro experiment, male SHR and WKY rats of 4 and 15 weeks of age were used. The microsome, cytosol and heavy mitochondria fractions from liver and kidney were isolated by ultracentrifuge. 10mg protein/ml of each subcellular fraction was incubated with 3H-aldosterone in Tris-HCl buffer at pH 7.4 containing NADPH, glucose-6-phosphate (G-6-P) and G-6-P dehydrogenase as described by Morris, D.J. et al. (Hypertension, 5 (suppl. I]: I-35-I-40, 1983.). Aldosterone and its metabolites synthesized were extracted with Sep-pak C18 cartridges and separated by HPLC on a reverse phase column. In vivo experiments, the urine of male SHR and WKY rats of 15 weeks old injected 10 microCi 3H-aldosterone intraperitoneally was collected for 48 hours, extracted and analyzed by HPLC. Peaks of steroids from SHR were compared with those from WKY. Incubation of aldosterone with liver microsomes yielded at least 10 polar and 3 less polar metabolites (A-ring reduced metabolites). SHR liver microsomes synthesized larger amounts of 3 polar metabolites than WKY liver microsomes. Liver cytosol, liver heavy mitochondria and kidney subcellular fractions mainly synthesized less polar metabolites, but failed to synthesize as much polar metabolites as liver microsomes. Kidney microsomes and cytosol from 4 weeks old SHR synthesized larger amounts of less polar metabolites compared to those from WKY. In vivo experiment, SHR of 15 weeks of age excreted larger amounts of 2 polar metabolites than WKY. The present study suggests that the difference of metabolism of aldosterone between SHR and WKY observed from an early stage in the liver and the target organ, kidney, may be associated with hypertension or its causative factors, and confirms that aldosterone will be metabolized to several polar and less polar forms by rat liver and kidney subcellular fractions.

Whether to determine the urinary kallikrein (UKK) level in the second trimester of pregnancy is valuable or not for the prediction of gestosis, especially of hypertension in the third trimester of pregnancy, was studied on 700 cases of pregnant women including 50 cases of gestosis. The main results obtained were as follows. Sixty cases of 610 non-gestotic women were low in UKK, and 17 of these cases later resulted in gestosis or preterm delivery. When a patient with mild gestosis and/or hypertension was admitted, the UKK level was elevated significantly in general by bed rest and a low-salt diet. The UKK level was more significantly lowered in threatened preterm delivery than in normal pregnant women (p less than 0.001). A close positive correlation was seen between UKK levels and prostaglandin E2 in urine in pregnant women (n = 30, r = 0.528). A relatively close correlation was seen between UKK levels and roll-over test results (n = 30). From these results, the authors reached the conclusion that to determine UKK in the second trimester of pregnancy is quite valuable in predicting not only gestosis and/or hypertension in the third trimester of pregnancy but also preterm delivery.

78 patients with essential hypertension (17 with borderline hypertension and 61 with hypertension) and 13 normal controls were examined to evaluate the relation between the urinary excretion rate of guanidinoacetic acid/creatinine (U-GAA/Cr), beta 2-microglobulin/creatinine (U-BMG/Cr), radio-sensitive microalbumin excretion rate/creatinine (U-AER/Cr), N-acetyl-D-glucosaminidase/creatinine (U-NAG/Cr) and renal function. There was no significant difference among these groups in creatinine clearance (Ccr), serum creatinine (Cr) or in U-BMG/Cr, U-NAG/Cr and U-AER/Cr. In hypertensive patients U-GAA/Cr was 49.2 +/- 16.7 mg/gCr, which was much lower than in controls (78.1 +/- 13.4) (p less than 0.001). The Ccr has a significant relation with U-GAA/Cr (r = 0.29, p less than 0.01) but not with U-AER/Cr, U-BMG/Cr nor U-NAG/Cr. In 44 patients, all of the above factors were investigated for 24 weeks during 4 kinds of anti-hypertensive treatment (10 with an angiotensin-converting enzyme inhibitor: A group, 11 with a beta-adrenergic blocker: B group, 12 with a Ca entry blocker: C group and 12 with diuretics: D group). In A and C group, U-GAA/Cr was elevated during therapeutic course. However, in B and D group it declined during treatment. These findings suggested that urinary excretion of GAA may be a more sensitive marker than AER, BMG or NAG in hypertension and angiotensin-converting enzyme inhibitor and Ca entry blocker can be useful in the treatment of patients with essential hypertension with renal damage.

To investigate the effects of dietary sodium on the peripheral dopaminergic mechanism, changes of unconjugated plasma dopamine(DA) and its related humoral factors were studied in 8 patients with essential hypertension(EH) and 8 age-matched normal controls(N) while they were receiving ordinary meals (Na, 130-180 mEq daily) followed by higher sodium (250-300 mEq daily) diets for a week. Plasma and urinary DA, norepinephrine(NE) and epinephrine(E) were measured by the highly sensitive COMT-mediated radioenzymatic procedure, which permits an accurate estimation of plasma DA as low as 5-6 pg/ml. Under high sodium diets, blood pressure and heart rate were not changed significantly in N and EH subjects. Urinary NE and E tended to decrease, while urinary DA increased significantly in both groups of subjects (p less than 0.05). There was a significant correlation between urinary sodium and DA (r = 0.590, p less than 0.001), but plasma DA failed to correlate significantly to urinary sodium or DA in all subjects. Plasma NE and E tended to decrease in both N and EH subjects, while plasma DA increased significantly (p less than 0.05) in EH from 7.2 +/- 0.8 pg/ml [mean +/- SEM] to 9.3 +/- 1.0 and slightly in N from 9.1 +/- 1.8 to 11.2 +/- 1.3. Plasma renin activity(PRA) and plasma aldosterone(PAC) were invariably decreased in all subjects, while plasma prolactin(PRL) remained unchanged. A significant correlation was observed between plasma DA and NE under ordinary meals (r = 0.733, p less than 0.01), but this correlation disappeared under high sodium diets. Plasma DA showed an inverse correlation to PAC (r = 0.351, p less than 0.05) under both dietary conditions. Upright posture induced a significant rise (p less than 0.05) in NE, E, DA, PRA and PAC with ordinary meals, but the responses of NE and PAC were apparently attenuated with high sodium diets. An intravenous injection of metoclopramide (MCP, 10 mg), a DA receptor antagonist, provoked a slight rise in plasma NE and DA with ordinary meals, of which responses were further enhanced with high sodium diets. MCP induced a definite rise in PAC and PRL in all subjects under both dietary conditions (p less than 0.01), while plasma E and PRA remained unchanged after MCP challenge. The results lend support to the view that unconjugated plasma DA could be a useful marker of peripheral dopaminergic activity, which might be a physiological regulator responsible for the suppression of aldosterone secretion and sympathetic nerve activity observed during high sodium intake.

Investigations of the changes in ambulation and water drinking behavior of SHR were carried out and an attempt was made to determine the influence of cold exposure on the systolic blood pressure (SBP) and urinary catecholamines excretion (UCA) in SHR. Twenty week old male SHR-Okamoto strain (approximately 350 g) were used. The automatic Ambulo-Drinkometer was used to determine ambulatory activity and water drinking in SHR. UCA was determined by the trihydroxyindole method using high performance liquid chromatography. Cold exposure was performed for a period of 24 hours in a room maintained between 0--3 degrees C. It was observed that ambulatory activity and water drinking of SHR in dark phase were higher than those in the light phase (P less than 0.001). Significant increases in urinary norepinephrine (UNE), urinary epinephrine (UE), and urinary dopamine (UDA) contents as well as in urine volume were observed in the dark phase as compared with those in the light phase. SBP was significantly elevated after cold exposure. It was also demonstrated that cold exposure produced a significant increase in UNE and UE both in light and dark phases. Significant increase in UDA in cold stressed SHR was observed in dark phase. Although at room temperature (20 +/- 2 degrees C) significant difference in UCA between light and dark phases was observed, during cold exposure no significant difference was apparent. These findings suggest that temperature modulation induces changes in circadian rhythms of urinary CA excretion in SHR.

The urinary aldosterone (ALD) was measured by aldosterone RIA kit and the following results were obtained. (1) We have known that ten percent solution of bovine serum albumin (BSA) instead of free serum LAD is used as the diluent of the urine in aldosterone RIA kit. (2) The upper limits of free ALD, HCl-ALD and beta-glucuronidase ALD in the urine diluted with 10% BSA were 1.6, 9.0 and 9.5 micrograms/dl respectively. (3) The values of urinary conjugated HCl-ALD and beta-glucuronidase ALD were approximately 3.5 times and 4 times as much as that of free ALD respectively. (4) A good correlation was obtained among the results of three methods (HCl-ALD, beta-glucuronidase ALD and free ALD). (5) No difference was found in the values of the urinary ALD in the healthy subjects and the patients with essential hypertension, kidney diseases and acute liver diseases.