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Aims Neurotropin® (NTP), an analgesic for chronic pain, has antihyperalgesic effects in specific alternation of rhythm in temperature (SART)-stressed rats. Previous studies have shown that SART stress induces hyperalgesia, as well as post-translational modification of proteins (including substrates for calpain, a calcium-dependent cysteine protease) in the mesencephalon of rats. To better understand the mechanism of action of NTP, we investigated whether SART stress activates calpain in the mesencephalon of rats and whether NTP inhibits this activation. Main methods Wistar rats were exposed to SART stress for 5 days. NTP (200 NU/kg/day) was administered intraperitoneally every day from the onset of SART stress. The mechanical pain threshold was measured using the Randall-Selitto test on the 6th day. Thereafter, the rat mesencephalon was immediately collected and calpain activity was examined using western blot analysis with a calpain cleavage site-specific antibody. Key findings SART stress induced hyperalgesia and increased the calpain activity in the mesencephalon of rats. In contrast, NTP treatment attenuated the hyperalgesia and prevented the increase in calpain activity in the mesencephalon of SART-stressed rats. Interestingly, a negative correlation was identified between calpain activity and mechanical pain threshold in SART-stressed rats treated with or without NTP. Furthermore, NTP inhibited calpain activity on mammalian uncoordinated-18 in rat mesencephalon homogenate and Ac-LLY-AFC as substrates in an in vitro cell-free system. Significance Our data demonstrate that NTP treatment prevents SART stress-induced calpain activation in the mesencephalon of rats and suggests that NTP-mediated antihyperalgesia is associated with an inhibition of calpain activity in the mesencephalon.

Objective Although the daily urinary sodium excretion (UNaV) is considered to provide the most reliable estimate of the daily sodium intake, it may be affected by salt loss due to sweating in summer. However, the seasonal variation in the daily UNaV associated with a normal lifestyle is unknown. Methods This study was performed in 348 outpatients from the Morioka region during three seasons: summer (summer 1), winter, and the following summer (summer 2). The daily UNaV (g salt/day) was estimated by the second morning urine method three times during each season. Seasonal variation was defined as a significant trend across the three seasons together with a significant difference between winter and both summers. Results In women, the daily UNaV was higher in winter (11.8±3.0 g salt/day) than in summer 1 (11.2±2.9 g salt/day) or summer 2 (11.0±2.9 g salt/day). In contrast, there was no marked seasonal variation in men. An analysis stratified by age (4 quartiles) identified seasonal variation in the older 2 quartiles of women (aged ≥68 years). In these women, the mean seasonal difference in the daily UNaV was 0.9 g of salt/day for both winter vs. summer 1 and winter vs. summer 2, while it was 0.1-0.8 g of salt/day in the other groups. Conclusion Seasonal variation in the daily UNaV only occurred in older female patients and was relatively small. This is evidence for restricting salt intake throughout the year and should reassure patients who are anxious about salt loss due to sweating in summer.

A 46-year-old woman was presented with mineralocorticoid excess syndrome and a large mass originating from the right adrenal gland. Clinical examination before right adrenalectomy revealed elevated serum concentrations of 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) both systemically and in the adrenal veins bilaterally. Histopathological and immunohistochemical analyses of the surgical specimen demonstrated adrenal hyperplasia of outer fasciculata cells, and the presence of cystic mass. The adrenalectomy ameliorated her blood pressure (BP) from 156/96 mmHg to 148/87 mmHg with a concomitant increase of serum potassium concentration from 3.1 mEq/l to 3.5 mEq/l. These results suggest that uni-adrenalectomy is, at least in part, effective in ameliorating not only BP but also potassium concentration in a patient of adrenal hyperplasia with excessive bilateral 18-OH-DOC production.

Estimation of salt intake by cumbersome 24-h urine collection is not suitable for individual patients because of substantial daily variation in intake. We developed the second morning urine (SMU) method for monitoring daily salt intake in healthy subjects by calculating the daily creatinine excretion and measuring the ratio of sodium to creatinine in the SMU specimen. To determine whether the SMU method was applicable to hypertensive patients, we tested it in hospitalized patients under an equilibrated sodium balance as a model population. This review focuses on application of the SMU method in hypertensive patients with mild target organ damage.

SUMMARY 1. Few studies have been reported concerning the effect of ageing on renal functional and vascular responses to various stresses during ordinary life. In the present study, we examined the effect of age on changes in renal sodium handling and renal vascular resistance (RVR) in response to standing from a supine position in subjects with normal renal function. 2. We selected 43 healthy males in the second through to the seventh decade of life and gave them a constant dietary sodium intake before the study period. Renal function was estimated by standard clearance methods with the subject in a state of euvolaemia. 3. The mean daily urinary excretion of sodium was 236 ± 22 mEq. Standing from a supine position was associated with significant decreases (P < 0.0001) in creatinine clearance (from 125 ± 18 to 117 ± 19 mL/min per 1.73 m2), sodium excretion (from 178 ± 29 to 97 ± 23 μEq/min) and fractional excretion of sodium (from 1.02 ± 0.19 to 0.60 ± 0.13%). A significant increase (P < 0.0001) in the RVR index (from 0.11 ± 0.03 to 0.14 ± 0.04 units) was noted. Univariate analysis indicated that while the change in RVR associated with standing was significantly diminished (P < 0.05) in older subjects, orthostatic changes in other parameters associated with standing were minimally influenced by age. 4. In conclusion, although the renal vascular response is impaired in advanced age, the renal functional response to orthostasis is otherwise maintained in healthy elderly subjects under conditions of normal sodium intake and clinical euvolaemia.

A 58-year-old woman was admitted to our hospital because of renal dysfunction that continued to progress even after withdrawal of cefdinir, the presumed cause of acute renal failure. Renal histologic findings included interstitial fibrosis accompanied by moderate lymphocytic infiltration, and tubular atrophy with reduced numbers of epithelial cells. Mesangial cells and glomerular basement membranes were nearly normal. Scintigraphy with 67gallium disclosed diffuse abnormal accumulation in both kidneys. A lymphocyte stimulation test with cefdinir was positive. The patient was diagnosed with acute tubulointerstitial nephritis caused by cefdinir. Serum creatinine concentrations continued to rise after withdrawal of the drug, but steroid therapy was effective in normalizing renal function.

A case of 46, XY pure gonadal dysgenesis with very tall stature was investigated. The 24-year-old, phenotypically female patient consulted our clinic because of linear growth persisting into adulthood. The patient was found to have no mutation or deletion of a sex-determining region of the Y chromosome, and also was found to have Graves' disease. Growth was arrested with height remaining at 187 cm after normalization of the thyroid function by treatment with an antithyroid agent, although follow-up to monitor growth was limited to 3 months. In some cases of gonadal dysgenesis, then, Graves' disease may contribute to an abnormally tall stature.

To determine the factors that affect seasonal variation in blood pressure (BP) in a fairly large number of patients with essential hypertension who stayed almost entirely indoors in a stable environmental temperature and who took a calcium channel blocker during the study. This prospective study of hypertensive patients was conducted during the summer and winter. BP was measured by ambulatory blood pressure monitoring; the indoor temperature was measured at the time of the BP measurement using an electrothermometer with the subject awake and indoors. Subjects comprised 38 men and 57 women. The subjects spent virtually the entire day indoors during both the summer (men, 22.1±1.6h; women, 23.0±0.9h) and winter (men, 23.0±0.9h; women, 22.9±0.9h). During the waking hours, the systolic/diastolic BPs were significantly higher during the winter than the summer. The differences were 8±9/4±5mmHg in men and 5±11/2±6mmHg in women; these values were not significantly different between men and women. No significant seasonal differences in BP during the sleeping hours were noted. There was a significant difference of approximately 6°C in the environmental temperature during waking hours, but there was no significant difference in urinary excretion of sodium or in exercise activity between the seasons. Only body height was significantly correlated with the winter increase in waking BP in both men and women, even after adjustment for potential confounding variables. Body height was a determinant of the increase in waking BP during the winter in hypertensive patients who lived almost entirely indoors. (Hypertens Res 2000; 23: 587-592)

The sympathoneural neurotransmitter norepinephrine (NE) is deaminated to 3,4-dihydroxymandelaldehyde (DHMAL) and subsequently converted to either 3,4-dihydroxymandelic acid (DHMA) or 3,4-dihydroxyphenylglycol (DHPG). In this study, we investigated the relative importance of aldose reductase versus aldehyde reductase in the formation of DHPG from DHMAL. The in vitro incubation of NE with aldose reductase in the presence of monoamine oxidase (MAO) resulted in the formation of DHPG, which was confirmed by mass spectrometry. Although aldehyde reductase also generated DHPG, its activity was much lower than that of aldose reductase. With northern blotting, the expression of both aldose reductase and aldehyde reductase was detected in rat superior cervical ganglia. However, with western blotting, only aldose reductase was immunologically detectable. Treatment of rats with aldose reductase inhibitors for 3 days increased the plasma level of DHMA. There was no correlation between the selectivity of inhibitors and effects on NE metabolite levels. A significant decrease in DHPG, however, was obtained only with an extremely high dose (9 mg/kg/day) of the nonselective inhibitor AL 1576. The present study confirmed that aldose reductase generates DHPG from NE in the presence of MAO. In rat sympathetic neurons, aldose reductase appears to be more important than aldehyde reductase for the formation of DHPG. However, when aldose reductase is inhibited, it appears that aldehyde reductase can compensate for the conversion of DHMAL to DHPG, indicating redundancy in the reduction pathway.

A 42-year-old man had biochemical and somatic abnormalities compatible with pseudohypoparathyroidism type I (PsHP) and also had high plasma renin activity (PRA). After 1, 25-dihydroxyvitamin D (calcitriol) supplementation the systolic/diastolic blood pressure, assessed by 24-hour non-invasive ambulatory blood pressure monitoring, was reduced from 145/96 mmHg to 128/85 mmHg with normalization of the serum calcium level and its related hormones, as well as decreased PRA. Calcitriol supplementation successfully reduced the blood pressure in this patient with PsHP and a high PRA, suggesting that calcium-related hormones and/or the renin-angiotensin system were involved in lowering the blood pressure.(Internal Medicine 38: 31-35, 1999)

After norepinephrine (NE) is deaminated by monoamine oxidase (MAO), the aldehyde formed is either metabolized to 3,4-dihydroxy-mandelic acid (DHMA) by aldehyde dehydrogenase or is converted to 3,4-dihydroxyphenylglycol (DHPG) by aldehyde or aldose reductase. The present study examined the effects of inhibition of aldehyde and aldose reductase on production of DHPG and DHMA in rats. Mean (+/- S.E.) baseline plasma concentrations of DHPG (4.73 +/- 0.21 pmol/ml) were 60-fold higher than those of DHMA (0.08 +/- 0.01 pmol/ml). Inhibition of aldose and aldehyde reductase reduced plasma DHPG concentrations to 1.88 +/- 0.14 pmol/ml and increased plasma DHMA to 4.43 +/- 0.29 pmol/ml; additional inhibition of MAO reduced plasma DHPG to 0.16 +/- 0.06 pmol/ml and DHMA to 0.19 +/- 0.02 pmol/ml. Inhibition of aldehyde and aldose reductase also increased brain tissue levels of DHMA from 8 +/- 2 to 384 +/- 47 pmol/g and decreased levels of DHPG from 70 +/- 9 to 44 +/- 5 pmol/g. The results show that DHMA is normally a minor metabolite of NE, but becomes a major metabolite after aldehyde/aldose reductase inhibition.

To evaluate the effects of prolonged intake of a high-sodium diet on glucose and lipid metabolism, we examined the relation of daily urinary sodium excretion to blood pressure, glucose metabolism, and lipid metabolism in 140 Japanese adults who lived in a region where the average daily consumption of sodium was high and stable during the past 15 yr; no subject had received any treatment for hypertension or metabolic disorders. Each subject was admitted to our health examination center for 2 d for measurement of blood pressure, sampling of blood, and glucose tolerance testing. A 24-h urine specimen was collected by each subject after discharge. Multiple regression analysis revealed that urinary sodium excretion was significantly independent of the mean blood pressure and was unrelated to the area under the serum glucose curve after glucose administration. The urinary sodium level was also unrelated to low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. The prevalence of hypertension in the group with a daily sodium excretion below 140 mEq (low sodium group) was 0%, while that in the group with a daily sodium excretion above 280 mEq (high sodium group) was 44%; this difference was significant (p < 0.01). No significant difference was observed in the prevalence of metabolic disorders between the two groups. Our results suggest that sodium intake has little influence on glucose and lipid metabolism but has a significant influence on blood pressure in normotensive and untreated hypertensive subjects who reside in an area with a relatively high sodium intake.

We investigated the correlations between the reduction in body weight (BW) induced by calorie restriction and reductions in blood pressure (BP) and improvement in metabolic disorders in overweight women with essential hypertension. After eating a standard diet (diet-I) for 2 weeks, women in the calorie-restricted group (n=25) received a low calorie diet for 2 weeks, and then standard diet-II for 1 week. Women in the calorie-nonrestricted group (n=13) ate standard diet-I for 5 weeks. The calorie-restricted group exhibited a significant reduction in BP in association with loss of BW; their levels of low-density lipoprotein cholesterol, and triglycerides levels, and their fasting levels of glucose and insulin were also reduced compared with the calorie-nonrestricted group. However, there were no significant differences in the level of high-density lipoprotein cholesterol, the areas under the 2-h glucose and insulin curves (AUCglu and AUCins), or the ratio of AUCglu to AUCins between groups. The change in BW was significantly correlated with a reduction in BP (r=0.62, p

The accuracy of the casual urine (CU) method for estimating daily salt intake was compared with the second morning urine (SMU) method and with 24-h urine collection (24 UC) method as the gold standard. Data were obtained from three previously reported studies, in which we evaluated the daily salt intake by the SMU method. Using SMU samples from 1315 outpatients, the estimated salt intake was lower with the CU method than the SMU method. In inpatients with a daily salt intake of 7, 8 or 18 g, the CU method was applied to SMU specimens. It underestimated salt intake compared with the 24-h collection method whereas the SMU method and 24 UC method gave similar results. In the present study, 24 UC was done and then urine was collected at 0800, 1100, 1400, 1700 and 1900 hours, with a daily salt intake of 6 g in 8 inpatients, 10 g in 11 inpatients or 15 g in 5 inpatients. In comparison with the 24 UC method, the CU method underestimated a high salt intake (15 g) when morning specimens were used and overestimated a low salt intake (6 g) when afternoon specimens were used. The correlation between the CU method and 24 UC method was weaker (R = 0.57) than that between the SMU method and 24 UC method (R = 0.85). In conclusion, the CU method is heavily influenced by the timing of urine collection and by the actual daily salt intake, so the SMU method provides a better estimate of individual salt intake.

Angiotensin II does not increase renal prostaglandin E2 in response to pressure reduction. Whether angiotensin II (Ang II) stimulates renal secretion of prostaglandin E2 (PGE2) synthesized in response to pressure reduction was examined. PGE2 and Ang II in aortic and renal venous plasma were measured before and during renal arterial constriction in anesthetized dogs, with or without an intrarenal arterial infusion of an Ang II antagonist, losartan potassium (1 mg/min), or saralasin (3 µg/min). In other anesthetized dogs, two doses of Ang II (30 and then 300 ng/min) were infused into the renal artery, and plasma Ang II levels and renal PGE2 secretion were measured. When renal perfusion pressure was reduced to 75 and 45mm Hg by constriction, the renal secretion of PGE2 increased seven- and fourfold, respectively. Ang II levels in the renal venous plasma increased from 6.6 ± 1.8 to 21.7 ± 7.4 and then 48.1 ± 15.3 pg/ml (both P < 0.05) as the pressure decreased. Neither losartan nor saralasin suppressed the response of renal PGE2 secretion to the pressure reduction. The intrarenal infusion of Ang II (30 ng/min) elevated the Ang II level in the renal venous plasma from 9.8 ± 4.6 to 33.7 ± 4.2 pg/ml (P < 0.01), but did not increase PGE2 secretion. The higher dose (300 ng/min) of Ang II increased it, but the Ang II level in the renal venous plasma was 166 ± 63 pg/ml. These results suggest that the greater part of the increased renal synthesis of PGE2 in response to pressure reduction is not mediated by Ang II.

1. To examine the effect of chronic administration of angiotensin I-converting enzyme (ACE) inhibitor on circulating angiotensin II (AII) concentration, 20 mg of lisinopril was administered once daily for 7 consecutive days to eight healthy volunteers. 2. Plasma ACE activity was inhibited to less than approximately 30% of the pretreatment level during the repeated administration. 3. Mean arterial pressure (MAP) was slightly but significantly reduced during the administration period. Plasma AII concentration measured by an established method using high performance liquid chromatography combined with a radioimmunoassay, however, was maintained at approximately the pretreatment level when it was measured at 24 h intervals after each administration of lisinopril. 4. With the gradual recovery of ACE activity following discontinuation of administration, the plasma AII concentration correlated with AI concentration (r = 0.46), and also with the product of AI and ACE activity (AI x ACE; r = 0.80), corresponding to the formula obtained from the kinetics of ACE activity. No correlation was observed between MAP and AII levels throughout the study period. 5. We conclude that in normal subjects repeatedly administered with ACE inhibitor, the AII level in the circulation is still determined by an elevated level of AI and any remaining ACE activity, thus maintaining AII at pretreatment levels. We confirmed that it is not necessary to achieve a decrease in plasma AII concentration through the chronic administration of ACE inhibitor in order to effectively lower blood pressure.

Rats exposed to a cold environment (4 degrees C) for 30 min every 1 h during the day and at night show a gradual decrease in the nociceptive threshold for pressure stimulation. Such hyperalgesia, referred to as repeated cold stress (RCS)-induced hyperalgesia, is stable for at least 4 h and maintained for 3 days only by exposing to cold overnight; thus, no adaptation to RCS is apparent. Hyperalgesia gradually returns over 4 days after cold exposure ceases. To determine whether three neuropeptides, substance P (SP), calcitonin gene-related peptide (CGRP) and galanin (GAL), which are present in the superficial dorsal horn including primary afferent terminals, would be responsible for RCS-induced hyperalgesia, we examined the effects of intrathecal injections of their antibodies (used as inhibitors of neuropeptide-mediated synaptic transmission) on the nociceptive threshold of RCS rats, and compared this with the antibody effect on carrageenan-induced hyperalgesia. An intrathecal injection of anti-SP antibody significantly inhibited the hyperalgesia of RCS rats as well as carrageenan-induced hyperalgesia, and slightly increased the nociceptive threshold of non-RCS rats. Anti-CGRP antibody produced an improvement in the hyperalgesia of RCS rats as well as carrageenan-induced hyperalgesia without having an effect on the nociceptive threshold of non-RCS rats. Although anti-GAL antibody significantly inhibited carrageenan-induced hyperalgesia, it did not affect the nociceptive threshold of RCS and non-RCS rats. The present results suggest that enhancement of synaptic transmission mediated by SP and CGRP, but not GAL, in the spinal dorsal horn is, at least in part, involved in RCS-induced hyperalgesia.

1. The effects of dietary sodium on blood pressure and levels of sodium, other electrolytes and noradrenaline (NA) in the cerebrospinal fluid (CSF) and blood of 15 patients with essential hypertension were studied. The CSF and blood sampling was carried out after 7 days of a high salt intake (16-18 g/day) and after 7 days of a low salt intake (1-3 g/day). 2. Blood pressure and sodium concentrations in CSF and serum were significantly higher in the high salt period than the low salt period (CSF Na+ concentration: 147.7 +/- 0.4 mmol/L vs 145.3 +/- 0.5 mmol/L; P less than 0.001). Levels of CSF pressure and potassium or calcium concentrations were not different between the two periods. Plasma NA and plasma renin activity (PRA) were lower and CSF NA levels tended to be lower in the high salt period. 3. The levels and the changes in sodium and NA in CSF were not significantly different between the salt-sensitive (n = 8) and the non-salt-sensitive (n = 7) subjects, but the changes in plasma NA and PRA were smaller in the salt-sensitive subjects. 4. These results indicate that the sympathetic nervous system is less suppressed in salt-sensitive subjects during high salt intake. This may be due to altered neural responsiveness to sodium loading rather than being greater increases in sodium concentration in the central nervous system.

This study was performed to elucidate the effect of a hypocaloric diet on blood pressure and sodium balance in overweight women with essential hypertension. Hospitalized patients were fed a hypocaloric diet (900 kcal/day) for 3 weeks after being fed a standard diet (SD) for more than 2 weeks. During the study, the sodium and potassium intake was kept constant as was the level of exercise activity. After the mean arterial pressure (MAP) and body weight had stabilized during the last week on the SD, caloric restriction significantly reduced the body weight by 1.5kg in the first week and by 0.8-0.9 kg in subsequent weeks, and reduced the MAP by 5mmHg and by 1-3mmHg, respectively. Although caloric restriction reduced the excretion of urinary norepinephrine and C-peptide, and elevated the serum levels of ketone bodies that would induce natriuresis, the urinary sodium excretion remained unchanged, indicating that sodium balance was unchanged even by caloric restriction. These results suggest that caloric restriction lowers the blood pressure in a short time with no significant change in sodium balance. (Hypertens Res 1992; 15: 137-142)

INAGAMI, T., MIZUNO, K., KAWAMURA, M., OKAMURA, T., CLEMENS, D.L. and HIGASHIMORI, K. Localization of Components of the Renin-Angiotensin System within the Kidney and Sustained Release of Angiotensins from Isolated and Perfused Kidney. Tohoku J. Exp. Med., 1992, 166 (1), 17-26-We found colocalization of renin, angiotensin (Ang) I and Ang II in juxtaglomerular (JG) cells of the kidney. Coexistence of Ang II in renin granules was demonstrated by electron microscopic immunogold labeling of these components. Coexistence of both Ang I and Ang II in the high density renin storage granules were also demonstrated by gradient centrifugation of renal homogenate. These findings supported the synthesis of Ang I and Ang II in juxtaglomerular cells. Isolated and cultured JG cells showed the synthesis of Ang I, Ang II and renin. Ang I and Ang II were secreted from isolated and perfused rat kidneys at steady rates over 2hr. Their secretion rates were proportional to that of renin. The rate of Ang II secretion from the kidney was higher than that from the vascular bed. Ang II was also found in renal lymph. These findings indicate that a large amount of Ang II is generated in JG cells by the intracellular action of renin and may play a significant role in the regulation of renal function.

The effects of brain natriuretic peptide (BNP) on renin secretion were evaluated in normal and hypertonic saline-infused kidneys of anesthetized dogs. In the normal kidney (N = 5), intrarenal infusion of porcine BNP-(1-26) (pBNP) at a dose of 50 ng/kg per min attenuated the renin secretion rate significantly to 9 +/- 27% of control without exerting a significant effect on mean arterial pressure (MAP), renal blood flow (RBF) or glomerular filtration rate (GFR); urine flow (V) was significantly increased to 260 +/- 33% of control and urinary excretion of sodium (UNaV) to 480 +/- 140% of control. In the hypertonic saline infusion group (N = 6), intrarenal infusion of hypertonic saline (20% w/v) at 0.5, 0.8, and 1.0 mEq NaCl/min caused a decrease in GFR and natriuresis in a dose-dependent manner. The renin secretion rate was attenuated by hypertonic saline infusion (1 mEq NaCl/min) to 87 +/- 31% of control. In another group (N = 6), administration of pBNP at a dose of 50 ng/kg per min during hypertonic saline infusion (1 mEq NaCl/min) increased the renin secretion rate to 196 +/- 57%, increased RBF to 160 +/- 13%, increased GFR to 137 +/- 22%, increased V to 221 +/- 29%, and increased UNaV to 218 +/- 29% of the values measured during hypertonic saline infusion. Our results indicate that BNP inhibits renin secretion through sodium delivery to the macula densa and effectively inhibits the tubuloglomerular feedback response that is activated by intrarenal hypertonic saline infusion.

The effects of a calcium-entry blocker, nicardipine, on intrarenal hemodynamics were studied in essential hypertension. A 4-week study was performed in eight patients with essential hypertension who were given a regular sodium diet in the first and third weeks, and a sodium-restricted diet in the second and fourth weeks. Nicardipine, 60 mg/d, was administered in the third and fourth weeks. The urinary sodium excretion rate (U Na V) was plotted on the y-axis against the mean arterial pressure (MAP) on the x-axis before and after the administration of nicardipine. Assuming the difference between MAP and the x-intercept of this renal function curve represents the effective filtration pressure across the glomerular capillaries, the intrarenal hemodynamics such as afferent arteriolar resistance (R A ) and efferent arteriolar resistances (R E ), glomerular pressure (P G ), and gross filtration coefficient (K FG ) were calculated. Although the MAP on regular salt diet was lowered from 125 ± 3 to 109 ± 2 mm Hg by nicardipine, neither the renal blood flow rate (RBF) (670 ± 40 mLlmin) nor the glomerular filtration rate (GFR) (79 ± 2 mLlmin) was altered. The R A was estimated to be reduced from 9,300 ± 900 to 7,400 ± 700 dyne·s·cm −5 ( P E (4,900 ± 400 dyne·s·cm −5 ), P G (50 ± 1 mm Hg), or K FG (0.180 ± 0.041 [mL/s]/mm Hg). Essential hypertension has been chararacterized by a prominent increase in R A , resulting in maintenance of normal P G . This Ca-entry blocker worked to normalize intrarenal hemodynamics in essential hypertension by dilating afferent arterioles alone. The reason why neither the RBF nor the GFR was increased by a longterm administration of nicardipine seemed due mainly to a parallel reduction in MAP with the reduced R A .

We investigated the possible role of renal prostaglandin (PG) E2 in natriuresis associated with supraventricular tachycardia (SVT). In five female patients with paroxysmal tachycardia, SVT was artificially induced and then stopped 60 min later. Before, during, and after SVT, plasma levels of arginine vasopressin and atrial natriuretic peptide (ANP) and the urinary excretion of sodium and PGE2 were measured. Polyuria was observed during SVT. However, natriuresis did not occur until immediately after the termination of SVT. During SVT, the plasma levels of arginine vasopressin tended to decrease. When SVT was terminated, the vasopressin levels increased significantly (p less than 0.01). Urinary excretion of PGE2 tended to decrease during SVT and then increased significantly (p less than 0.01) after SVT ended. Urinary excretion of sodium was correlated (r = 0.699, p less than 0.001) with the urinary excretion of PGE2. Plasma ANP increased during SVT, but there was no correlation with urinary sodium excretion. These results suggest that renal PGE2, the biosynthesis of which may be stimulated by a increase in plasma vasopressin, is an important factor contributing to the natriuresis observed after the end of SVT.

The present study was designed to examine and compare the acute effects of lisinopril (20 mg) and enalapril (10 mg) after a single oral administration on the inhibition of the renin-angiotensin system (RAS) in eight normal subjects. Serum concentration of lisinopril and enalaprilat, an active metabolite of enalapril, reached the respective maximal levels at 6 and 4 hr after administration of the drugs. At 24 hr, the serum concentration of lisinopril was higher than that of enalapril; thus the rate of disappearance of lisinopril was retarded, in comparison to that of enalapril. The reduction of serum angiotensin I converting enzyme (ACE) activity was consistent with the pattern of increase of concentration of the drugs in the serum. However, with these two drugs, the concentration of plasma ANG II was decreased in a similar manner, and it returned to the pretreatment level within 24 hr. Thus, there was no significant difference in ANG II levels throughout the 24 hr-study between the lisinopril and enalapril treatment. The results indicate that a single administration of 20 mg lisinopril and 10 mg enalapril show similar potency for lowering the circulating ANG II level, although lisinopril exerts a more sustained inhibition of serum ACE activity. The measurement of ANG II provides useful informations for evaluating the efficacy of ACE inhibitors for the inhibition of circulatory RAS.

Kawasaki et al. developed a spot urine method (SUM) for evaluating daily salt intake using one pre-breakfast sample obtained after initial voiding upon arising. Their subjects were healthy persons who were not taking any regular medications. To determine whether SUM can be successfully used for patients taking antihypertensive drugs, we estimated daily salt intake in 73 hypertensive patients by SUM and by a food consumption method (FCM) when they were at home, and also by SUM in the hospital with a defined intake of 7 g of sodium chloride (NaCl). Forty-one patients took oral antihypertensive medications once daily, while 32 patients took none. Mean daily salt intakes by SUM during admission were 7-8 g of NaCl in both groups (95% confidence intervals: 5.0-10.6 g in the medication group; 5.2-11.1 g in the no-medication group), which corresponded well to the diet. In contrast, ambulatory daily salt intake by SUM varied widely (95% confidence intervals: 5.5-20.7 g in the medication group; 7.6-22.8 g in the no-medication group). However, the daily salt intakes determined by SUM and FCM correlated significantly with each other in the medication group (r=0.69, p

A 47-year-old man presented with polydipsia, which had had since childhood, and recent onset of hypertension. Genetic analysis proved that he had nephrogenic diabetes insipidus caused by a novel mutation (deletion of 6 amino acids between G107 and C112) in the vasopressin V2 receptor gene. Results of 24-hour blood pressure monitoring disclosed a greater dipping pattern and greater blood pressure variability during waking hours than in male patients with only essential hypertension. This characteristic blood pressure profile may result from daily occurrence of free water depletion, as further observation indicated that water deprivation was associated with a reduction in blood pressure.

OBJECTIVE The circadian rhythm of blood pressure in patients with aldosterone-producing adenoma (APA) is not well understood. We evaluated the circadian blood pressure rhythm in such patients by comparison with that in patients with essential hypertension (EHT). The latter are characterized by a nocturnal blood pressure decline, the so called 'dipping' blood pressure pattern. DESIGN AND METHODS A total of 12 patients with APA and 36 patients with EHT who were matched by age and sex, and who had no severe organic disorders, were hospitalized to control their diet (low sodium) and activities. Ambulatory blood pressure monitoring was conducted for 24 h. The 24-h blood pressure was divided into waking blood pressure (0600-2130 h) and sleeping blood pressure (2200-0530 h). RESULTS The two groups showed no significant differences in age, sex, serum creatinine, plasma glucose, daily urinary sodium excretion, and left ventricular mass index. Although the 24-h mean blood pressure was higher in APA (112 +/- 8 mmHg) than EHT (102 +/- 12 mmHg), the dipping mean blood pressure ratio (%), which was calculated from the sleeping and waking blood pressures, did not differ significantly between the two groups (93.2 +/- 5.4 versus 92.8 +/- 5.9). CONCLUSION The dipping ratio of blood pressure in patients with APA resembled that of patients with EHT. Variables that would influence the circadian rhythm of blood pressure were controlled during study. The results suggest that a circadian blood pressure in patients with APA is of the dipping type, characterized by a nocturnal blood pressure decline, when a low sodium diet is ingested.

In a 39-yr-old female patient with Bartter's syndrome, vascular responsiveness to angiotensin II and phenylephrine was studied. Pressor responses to angiotensin II and to phenylephrine were markedly decreased prior to treatment and were improved by administration of indomethacin, dextran, KCI, captopril, propranolol or pindolol. Moreover, the responses of total peripheral vascular resistence to angiotensin II and phenylephrine were markedly decreased before treatment and were improved by the treatment. A relatively low fractional distal chloride reabsorption was found, and that was not changed after the administration of KCI or indomethacin. The results of this patient were compatible with the primary cause of Bartter's syndrome, defective chloride reabsorption at the loop of Henle, but the possibility of an abnormality in the vascular wall could not be denied.(Internal Medicine 31 : 134-139, 1992)

While serum magnesium (Mg) level is increased in patients with end-stage renal disease (ESRD), it is decreased in renal transplant recipients (TR) receiving ciclosporin. This study was performed to examine the cation metabolism of red blood cells (RBC) in these patients. Intracellular free Mg was measured with 31P-nuclear magnetic resonance spectrometry, and ouabain-sensitive sodium (Na) efflux rate (Eos) was measured from the increase in RBC-Na concentration when RBC were incubated in the presence of ouabain. The ouabain-sensitive Na efflux rate constant (ERCos) was obtained by dividing Eos by RBC-Na concentration. RBC free Mg and ERCos were significantly higher in the TR group than in the ESRD group. There was a significant correlation between RBC free Mg and ERCos (r = 0.474, p less than 0.01). These results support the views that the regulation mechanism for intracellular free Mg is different from that for extracellular Mg in patients with renal disease, and intracellular free Mg modulates Na pump activity of RBC.

Responses of renin release and blood pressure to aspirin DL-lysine (ASP) were examined to find out if the responses could help in the differentiation between unilateral renovascular hypertension (RVH) and hyperreninemic essential hypertension (EHT). The two studies involved ten patients with unilateral RVH, eight with hyperreninemic EHT, and five with hyporeninemic EHT. In a radiological study, before and 30 min after an intravenous injection of ASP (18 mg/kg), renal venous and abdominal aortic plasma was sampled and assayed for prostaglandin (PG) E2 and plasma renin activity (PRA). Systemic blood pressure was measured serially. The reproducibility of the responses to ASP was confirmed in a bedside study. In unilateral RVH, ASP suppressed renin release from the stenotic kidney and reduced the renal vein PRA ratio to less than 1.5 via the inhibition of PG synthesis, which is accelerated in that kidney. The mean suppression of aortic PRA at this dose of ASP was 35% in these patients, and their blood pressure decreased in proportion to the suppression of PRA. However, in the two EHT groups, ASP elevated the mean blood pressure. The renal synthesis of PGE2 was inhibited by ASP in all patients, but the suppression of PRA, while small, was significant (19% in the aorta) in the patients with hyperreninemic EHT, and not significant in patients with hyporeninemic EHT. The different responses of blood pressure and PRA to ASP between RVH and EHT were reproducible in the bedside study.(ABSTRACT TRUNCATED AT 250 WORDS)

To ascertain the involvement of galanin in nociceptive transmission in the spinal dorsal horn, we examined the effects of intrathecal injections of porcine galanin and its antiserum on behavioral nociceptive responses of the rat, using the paw-pressure and paw-radiant heat tests. An intrathecal injection of antiserum against porcine galanin reversed the decreased nociceptive threshold for mechanical, but not thermal, stimulation of the carrageenintreated hind paw of rat, with no effect on the nociceptive threshold of the non-inflamed hind paw. Rat galanin as well as porcine galanin suppressed the binding of [125I]porcine galanin to the antiserum, a finding suggesting that the antiserum can bind rat galanin. An intrathecal injection of porcine galanin (0.1 and 1 nmol, but not 0.01 nmol) decreased the mechanical nociceptive threshold of the rat hind paw with no effect on thermal nociception. These results suggest that galanin present in the dorsal horn is involved in the facilitation of mechanical, but not thermal, nociceptive transmission.

To examine the mechanisms of H+ transport in the mid-inner medullary collecting duct of hamsters, we measured the intracellular pH (pHi) in the in vitro perfused tubules by microscopic fluorometry using 2',7'-bis(carboxyethyl)-carboxyfluorescein (BCECF) as a fluorescent probe. In the basal condition, pHi was 6.74 +/- 0.04 (n = 45) in HCO3(-)-free modified Ringer solution. Either elimination of Na+ from the bath or addition of amiloride (1 mM) to the bath produced a reversible fall in pHi. After acid loading with 25 mM NH4Cl, pHi spontaneously recovered with an initial recovery rate of 0.096 +/- 0.012 (n = 23) pH unit/min. In the absence of ambient Na+, after removal of NH+4, the pHi remained low (5.95 +/- 0.10, n = 8) and showed no signs of recovery. Subsequent restoration of Na+ only in the lumen had no effect on pHi. However, when Na+ in the bath was returned to the control level, pHi recovered completely Amiloride (1 mM) in the bath completely inhibited the Na(-)-dependent pHi recovery. Furthermore, elimination of Na+ from the bath, but not from the lumen, decreased pHi from 6.97 +/- 0.07 to 6.44 +/- 0.05 (n = 12) in the HCO3-/Ringer solution or 6.70 +/- 0.03 to 6.02 +/- 0.5 pH unit/min in the presence of CO2/HCO3-, whereas it did not recover in the absence of CO2/HCO3-.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether biosynthesis of somatostatin is enhanced in the primary sensory neurons by inflammatory pain, we examined the effects of adjuvant inoculation on the content of immunoreactive somatostatin, mainly composed of somatostatin-14 and somatostatin-28, in the dorsal root ganglia and the spinal cord of the rat. The adjuvant inoculation, which produced long-lasting inflammation and hyperalgesia, increased the content of immunoreactive somatostatin, especially somatostatin-14, in the dorsal root ganglia at L4–L6 levels with no change in the dorsal and ventral horns of lumbar enlargement. Such an increase was enhanced by an intrathecal injection of colchicine (0.2 mg) that inhibits axonal flow of somatostatin. Chronic administration of the anti-inflammatory analgesic, sodium diclofenac (3 mg·kg−1·d−1), abolished an adjuvant-induced increase in the content of immunoreactive somatostatin in the dorsal root ganglia. These results suggest that the turnover (biosynthesis and axonal flow) of somatostatin in the primary sensory neurons is enhanced in the presence of persisting inflammatory pain, and support the idea that somatostatin-containing primary afferents are involved in the transmission of pain in the spinal dorsal horn.

Trypsin-activated renin (inactive renin) was detected in the break-through fraction when dog plasma or renin extracted from renin granules (stored renin) was applied to a pepstatin column, respectively. The appearance of the renin activity by trypsin treatment was not due to acid protease. Production of angiotensin I from homologous renin substrate by the trypsin-activated renin was proportional to the time of incubation. The trypsin-activated renin had an affinity for the pepstatin column. The maximum amount of trypsin-activated renin was obtained with incubation for 15 min at 37 degrees C at 1000 micrograms/ml in plasma or at 100 micrograms/ml in case of stored renin. The ratio of inactive to active renin was calculated to be 1.6 or 0.002 in plasma or stored renin, respectively, under conditions of a standard sodium diet.

To clarify the role of renal prostanoid in hyperreninemia and high blood pressure in human renovascular hypertension, we measured prostaglandin E2 and renin activity in renal venous and abdominal aortic plasma before and after the intravenous administration of the cyclooxygenase inhibitor, aspirin DL-lysine. Subjects were six patients with unilateral renovascular hypertension and six with essential hypertension. In patients with renovascular hypertension, prostaglandin E2 concentration in renal venous plasma from the stenotic kidney was 9.25 +/- 1.48 pg/ml, which was significantly higher (p less than 0.01) than the concentration in the renal venous plasma from the normal kidney (4.97 +/- 1.02 pg/ml) or in the aortic plasma (2.59 +/- 0.15 pg/ml). Plasma renin activity was also higher in the renal vein of the stenotic kidney than in the other two sites. The stenotic side/normal side ratio of the renal venous prostaglandin E2 correlated significantly with a renin ratio greater than 1.5 (r = 0.8211, p less than 0.05). Intravenous injection of aspirin DL-lysine (18 mg/kg) 30 minutes later markedly suppressed prostaglandin E2 and renin levels at all sites and clearly lowered arterial blood pressure (mean: from 120 +/- 6 to 110 +/- 5 mm Hg, p less than 0.01). The reduction in blood pressure correlated significantly with the suppression of plasma renin activity in the aorta (p less than 0.05) and in the renal vein of the stenotic kidney (p less than 0.01). Conversely, in patients with essential hypertension, aspirin had little effect on renin levels and increased mean blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Kallikrein-kinin and renin-angiotensin systems in rat renal lymph. Rat renal lymph contains 254 ± 17 ng/ml (x ±SEM, N = 20) of immunoreactive glandular kallikrein. Like the immunoreactive glandular kallikrein in plasma, it is biologically inactive. Gel filtration of renal lymph reveals profiles for immunoreactive glandular kallikrein, protein, and inhibition of trypsin and kallikrein which resemble those seen for plasma except that high molecular weight plasma components are reduced or missing in renal lymph. In contrast, gel filtration of thoracic lymph reveals immunoreactive glandular kallikrein and protein profiles which are indistinguishable from those seen with plasma. Renin levels are 170-fold higher in renal lymph than in thoracic lymph while angiotensin-converting enzyme levels are only 16% those of thoracic lymph. In keeping with the high renin and low converting enzyme activities, renal lymph contains high levels of angiotensin I. Immunoreactive glandular kallikrein levels in renal lymph, thoracic lymph and plasma do not show the striking differences observed for renin.Les systèmes kallikréine-kinine et rénine-angiotensine dans la lymphe rénale de rat. La lymphe rénale de rat contient 254 ± 17 ng/ml (xSEM, N = 20) de kallikréine glandulaire immunoréactive. Comme la kallikréine glandulaire immunoréactive plasmatique, elle est biologiquement inactive. La filtration sur gel de lymphe rénale révèle des profils de kallikréine glandulaire immunoréactive, de protéines, d'inhibiteurs de la trypsine et de kallikréine qui ressemblent à ceux vus pour le plasma, à l'exception que des constituants plasmatiques de haut poids moléculaire sont diminués ou absents dans la lymphe rénale. A l'opposé, la filtration sur gel de lymphe thoracique révèle des profils de kallikréine glandulaire immunoréactive et de protéines qui ne sont pas distinguables de ceux du plasma. Les niveaux de rénine sont 170 fois plus élevés dans la lymphe rénale que dans la lymphe thoracique, tandis que les niveaux d'enzyme de conversion de l'angiotensine sont seulement 16% de ceux de la lymphe thoracique. En même temps qu'une rénine élevée et que de faibles activités d'enzyme de conversion, la lymphe rénale contient des niveaux élevés d'angiotensine I. Les niveaux de kallikréine glandulaire immunoréactive dans la lymphe rénale, la lymphe thoracique et le plasma ne montrent pas les différences frappantes observées pour la rénine.

1. Angiotensin (ANG) levels were measured in the cerebrospinal fluid of 15 patients with essential hypertension on a high sodium diet for 1 week and on a low sodium diet for a further week. ANGs were determined using a system of extraction by Sep-Pak cartridges followed by h.p.l.c. combined with radioimmunoassay. 2. Sodium depletion resulted in increases of ANG II in the cerebrospinal fluid from 1.16 ± 0.38 (sem) to 1.83 ± 0.43 fmol/ml (P < 0.01) and of ANG III from 0.65 ± 0.11 to 0.86 ± 0.15 fmol/ml (P < 0.01). 3. The ANG II level in the cerebrospinal fluid was found to be unchanged and recovery of added ANG II was approximately 90%, even after incubation for 3 h, on both diets. Thus, it is unlikely that ANG II is produced or degraded in the cerebrospinal fluid in vitro. 4. There was no significant correlation between the cerebrospinal fluid and the plasma ANG II concentration on the low sodium diet. 5. These results suggest that the cerebrospinal fluid ANG II level increases with sodium depletion, and that the effect of the level of ANG II on the activity of the angiotensin-forming system in the central nervous system may be assessed by determination of ANG II in the cerebrospinal fluid in patients with essential hypertension.

1. A soluble fraction of renal cortical homogenate (cytosol) and renin extracted from isolated renin granules of the dog kidney were kept at 0°C. 2. Although the molecular weight of the renin in the cytosol on day 1 was estimated to be about 40 000 by gel filtration, the renin was completely converted into a higher—molecular—weight form (60 000) by day 7. The renin in the granules kept its molecular size of 40 000 during cold storage. 3. This type of molecular—weight conversion could be performed without protease inhibitors. 4. Dithiothreitol neither inhibited the conversion into the higher—molecular—weight form of renin during cold storage nor led to a reduction in the molecular weight of renin, although the oxidation of thiol groups has been proposed as the mechanism for the molecular—weight conversion of renin. 5. Keeping a mixture of renin from the granules and crude renin—binding substance at 0°C for 7 days resulted in the conversion of the renin into the higher—molecular—weight form, indicating that the renin—binding substance we have previously described is required for the conversion during cold storage. 6. Acidification caused the higher—molecular—weight form of renin formed in the cytosol to change to the lower—molecular—weight form, with a concomitant increase in activity of about 50%.

We examined the inactive to active renin ratio in the renin granules of the cadaver kidneys and the plasma in patients with diabetic nephropathy. The inactive renin in the break-through fraction when the plasma or the renin from the renin granules was put into a pepstatin column was determined. The inactive renin in this fraction was activated by trypsin. Concerning plasma, the inactive to active renin ratio was 90 in the patients and 9 in the normal subjects. On the other hand, this ratio was 0.29 in the patients' kidneys and 0.28 in the control kidneys. These results suggest that the increase of the inactive to active renin ratio in plasma of diabetic nephropathy does not result from the change of the renin storage in the kidneys.

We determined concentrations of atrial natriuretic peptide (ANP), angiotensin (Ang), norepinephrine (NE) and electrolyte in plasma and cerebrospinal fluid (CSF) to study possible roles of these substances within the brain in human hypertension. Blood and CSF samples were obtained from 10 patients with mild to moderate essential hypertension (EHT) aged 40-65 y and 10 age-matched normotensive subjects (NT) on a regular salt diet (8 g/day). Levels of ANP, NE, Na, K, Ca and Cl in CSF and plasma were comparable between EHT and NT. Plasma renin activity, plasma and CSF Ang II were lower in EHT than NT. CSF Ang III tended to be lower in EHT. There was no correlation between CSF and plasma ANP, or between CSF and plasma Ang II. Our results indicate that CSF levels of ANP may not be altered in middle aged patients with mild to moderate hypertension. It is also suggested that Ang II, NE and sodium in the central nervous system may not have important roles in hypertension of those patients.

Red cell sodium (RBC-Na+) concentrations were measured using 23Na nuclear magnetic resonance (NMR), without the destruction of erythrocyte membranes. Subjects were categorized into four groups: 20 normotensive subjects (NT group), 20 age-matched essential hypertensive patients (EHT group), 10 patients with primary aldosteronism (PA group), and 18 patients treated with digoxin (DIG group). Although RBC-Na+ concentrations were similar between the NT group (6.14 +/- 0.80 (Mean +/- SD) mmol/l) and the EHT group (5.92 +/- 0.99), they were significantly higher in both the PA group (7.55 +/- 0.88, p less than 0.001) and the DIG group (8.43 +/- 3.81, p less than 0.02). In the PA group, RBC-Na+ concentrations decreased significantly after resection of the adenoma, and there was an inverse relationship between serum potassium and RBC-Na+ concentrations (r = -0.65, p less than 0.01). In the DIG group, RBC-Na+ concentrations tended to increase in proportion to serum digoxin levels (r = 0.53, p less than 0.05). These results support the view that RBC-Na+ concentrations are determined primarily by Na+/K+-pump activity of red cell membranes. This study showed also that Na+ NMR is an useful method determining intracellular Na+ concentrations.

We examined the diuretic effects of a second infusion of atrial natriuretic polypeptide (ANP). Intrarenal infusion of ANP (50 ng X kg-1 X min-1) for 30 min to anesthetized dogs had no significant effect on mean arterial blood pressure (MABP), renal blood flow (RBF) and glomerular filtration rate (GFR), whereas there was an increase in urine flow (V) and urinary excretion of sodium (UNaV) from 7.5 +/- 1.5 to 34.1 +/- 9.4 microliters/g X min, from 0.97 +/- 0.20 to 4.38 +/- 1.32 microEq/g X min, respectively. When the same dose of ANP was infused 1 h after the first administration, V and UNaV were increased from 12.4 +/- 1.8 to 62.5 +/- 18.8 microliters/g X min, from 1.72 +/- 0.57 to 7.18 +/- 2.68 microEq/g X min, respectively. A second infusion of ANP caused a greater absolute increase in UNaV than did the first infusion but proportionally the increase in UNaV with the second ANP infusion was much the same. The present study shows that acute ANP infusion has no tachyphylaxis on the natriuretic response. These data will aid in establishing a bioassay for natriuretic response in vivo, thereby leading to elucidation of the physiological action of ANP.

To examine the influence of dietary sodium, prostaglandin, and captopril on vascular reactivity, 12 patients with essential hypertension (EH) and seven normotensive subjects (NT) were given a high sodium diet and thereafter a low sodium diet, each for ten days. Indomethacin (IND) (150 mg/d) was administered during the last three days of each dietary period. Blood pressure and cardiac output (CO) (by impedance cardiography) were measured during the angiotensin II (Ang II) infusion before and after the IND treatment of each dietary period. In eight patients with EH, captopril 100 mg was given before Ang II infusion. EH patients were classified as either salt sensitive (SS) or nonsalt sensitive (NSS). The mean blood pressure (MBP) response to Ang II was significantly higher on high sodium intake than on low sodium intake in NSS and NT, but not in SS. IND significantly increased the MBP response to Ang II on low sodium intake in NSS and NT, but not in SS. IND significantly increased the TPR response to Ang II on low sodium intake, remarkably in NSS and NT compared with SS. Salt sensitivity (% decrease in MBP from high to low sodium intake) highly correlated with the increase in the TPR response to Ang II by IND on low sodium intake (r = -0.90). After captopril administration, IND still increased the MBP and TPR response to Ang II on low sodium intake. These results suggest that the modulation of the vascular responsiveness to Ang II by prostaglandins is altered by sodium balance and salt sensitivity in EH.

A normal size form of renin, which seems to be a storage form in renin granules, changed neither in molecular weight nor activity by acidification to pH 3.0. High molecular weight (HMW) renin fractionated by gel chromatography from crude renal extract prepared with thiol group blockers was converted into normal size renin by acdification, accompanied with an increase in renin activity by about 50%. The molecular weight conversion by acidification appeared due to destruction or loss of binding ability of the renin binding substance which was present in the cytosol of renal cortical tissue. Renin and renin binding substance could combine into HMW renin at neutral pH in the presence of thiol group blockers and renin activity decreased.