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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.

In this section of the Report of the Salt Reduction Committee of the Japanese Society of Hypertension, the target level of dietary salt reduction and its scientific evidence, present status of salt consumption in Japan, salt-reducing measures/guidance methods in individuals and population strategies to reduce salt intake are introduced. In the Dietary Reference Intake for the general population in Japan (2010 version), the target levels of salt restriction in men and women were established as less than 9.0 per day and 7.5 g per day, respectively. The Japanese Society of Hypertension Guidelines for the Management of Hypertension 2009 recommended the target level of dietary salt restriction in patients with hypertension as less than 6 g per day. However, the National Health and Nutrition Survey of Japan in 2010 reported that the mean salt intake in adults was 10.6 g per day (men: 11.4 g per day and women: 9.8 g per day). To effectively decrease salt intake in Japan, it is necessary to reduce the consumption of high-salt foods (especially traditional foods) and replace high-salt seasonings (soy sauce and so on) with low-salt alternatives. Health-care professionals must effectively perform salt-reduction guidance for hypertensive patients in hospitals/administrative organizations. To promote population strategies for salt reduction in the whole society of Japan, social strategies, such as administrative policies, companies' cooperation and educational staff's cooperation, are necessary.

Aims In this study, we investigated the combined effect of Neurotropin® and pregabalin for L5-spinal nerve ligation (L5-SNL) model in rats and thiopental-induced sleep in mice. Main methods The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. The hindpaw withdrawal threshold was measured by application of von Frey filaments. Thiopental sodium was intravenously administered in mice and sleeping time was measured. In L5-SNL rats, an isobolographic analysis was performed to clarify the combined antiallodynic effect of Neurotropin and pregabalin 14 days after ligation in rats. In isobolographic analysis and thiopental-induced sleep test, Neurotropin and pregabalin were orally administered to coincide with the timing of the peak effect of each drug. Key findings Neurotropin (50–200 NU/kg) and pregabalin (2.5–10 mg/kg) showed a dose-dependent antiallodynic action in L5-SNL rats. The antiallodynic effect of pregabalin was reversed by intrathecal injection of yohimbine or ondansetron. Isobolographic analysis suggested that the combined antiallodynic effect of Neurotropin and pregabalin in L5-SNL rats may have been more than a mere additive effect. Neurotropin (50–400 NU/kg) had no effect on thiopental-induced sleeping time whereas pregabalin (30–100 mg/kg) significantly prolonged it. When the dose of pregabalin was 30 mg/kg, Neurotropin (50–400 NU/kg) did not further exacerbate the prolongation effect of pregabalin on thiopental-induced sleep. Significance It was suggested that when Neurotropin was administered in combination with pregabalin, it might provide more effective pain relief than that obtained with each agent alone in neuropathic pain without aggravating adverse effects of pregabalin.

OBJECTIVE To investigate the seasonal variation of severe hypoglycemia in hospitalized elderly patients. METHODS Among the patients hospitalized in our department between 2004 and 2010, we analyzed the records of 67 patients who required emergency admission for severe hypoglycemia and were aged 60 years or older. Comparisons were made between those admitted during the warm season (April-September) and those in the cold season (October-March). PATIENTS The mean age of the 67 patients was 76±8 years, including 45 men and 22 women. Twenty-four patients were admitted in the warm season and 43 patients were admitted in the cold season, with the average annual number being 3.4±1.9 and 6.1±2.8, respectively (p

The second morning urine (SMU) method was developed to evaluate daily salt intake, but the posture that should be adopted until the SMU collection remains unclear. This study investigated the influence of posture in hypertensive patients who underwent this test. The subjects were 100 patients who could collect 24-h urine samples correctly and were on a diet containing 7 g of salt per day. Their daily salt intake was estimated for three consecutive days in the recumbent, sitting, and sitting and standing positions (one posture each day). Estimated salt intake in the recumbent position (10.9+/-2.4 g day(-1)) was higher than in the sitting position (7.5+/-2.0 g day(-1)) and the sitting and standing position (6.3+/-1.7 g day(-1)). The salt intake estimated in the sitting and standing position was similar to that obtained by 24-h urine collection (6.3+/-1.6 g day(-1)) and was significantly (r=0.44, P0.05) correlated with the 24-h urine value. The actual difference in estimated salt intake between the two methods was 0.0+/-1.7 g day(-1). There were no significant differences in estimated salt intake between the two methods in patients taking different classes of antihypertensive drugs. In conclusion, adopting the sitting and standing position until the SMU collection is important for the correct estimation of daily salt intake, and this method could replace the 24-h collection method because of its convenience, especially in outpatients.

Neurotropin®, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug for treatment of chronic pain. In this study, we investigated the analgesic mechanisms of Neurotropin in the adjuvant-induced arthritic rat, a chronic pain model with inflammation. Neurotropin caused dose-dependent inhibition of hyperalgesia in the adjuvant-induced arthritic rat after single intravenous (10 – 100 NU/kg) and oral (30 – 200 NU/kg) administration. The analgesic effect of Neurotropin (intravenous 100 NU/kg and oral 200 NU/kg) was significantly inhibited by intrathecal injections of the α2-adrenoceptor antagonist yohimbine (30 nmol/animal) and the selective 5-HT3 serotonin receptor antagonist MDL72222 (30 nmol/animal), and slightly inhibited by the non-selective serotonin receptor antagonist methysergide (100 nmol/animal). The results suggest that the analgesic action of Neurotropin is at least in part due to the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways. Neurotropin may be useful for the clinical management of chronic pain diseases such as a rheumatoid arthritis and osteoarthritis. Keywords:: Neurotropin, adjuvant-induced arthritis, descending pain inhibitory pathway, serotonin receptor, α2-adrenoceptor

Aims Although the clinical use of Neurotropin ® as an analgesic for chronic pain has been firmly established, its analgesic mechanism is still unclear. In this study, we investigate the direct effects of Neurotropin using an electrophysiological method. Main methods Blind patch-clamp recordings were made from rat locus coeruleus (LC) and periaqueductal gray (PAG) neurons in brainstem slices of normal rats. The effects of intracerebroventricular (icv) injection of Neurotropin on nociceptive transmission were recorded from spinal substantia gelatinosa (SG) neurons in fifth lumbar spinal nerve-ligated (L5-SNL) rats using an in vivo patch-clamp method. Key findings Neurotropin (0.2–1.0 NU/mL) dose-dependently increased the firing rate in noradrenergic LC neurons of normal rats. Under the voltage-clamp condition, Neurotropin induced an inward current in 90% of LC neurons that was not affected by tetrodotoxin or an injection of GDP-β-S (G protein inhibitor) through recording pipettes. In contrast, Neurotropin had no effects on all PAG neurons tested. Using in vivo patch-clamp recordings, the icv injection of Neurotropin inhibited both frequency and amplitude of pinch-evoked excitatory postsynaptic currents of SG neurons in L5-SNL rats. These results suggest that Neurotropin directly excites the descending noradrenergic LC neurons and inhibits nociceptive transmission in the spinal dorsal horn. Significance This study is the first direct demonstration that Neurotropin activates the noradrenergic descending pain inhibitory systems, and this would reinforce the usefulness of Neurotropin in the treatment of human neuropathic pain.

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 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)

Neurotropin, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug in Japan. Its analgesic effect has been demonstrated by reduced mechano-nociception in hyperalgesic rats exposed to SART-stress (a repeated cold stress) for 5 days. In order to clarify the mechanism of the analgesic effect of neurotropin at the spinal cord level, we examined the effects of several neurotransmitter receptor antagonists given by intrathecal (i.t.) injection on the antinociceptive effect of intraperitoneally (i.p.) injected neurotropin [100 and 200 Neurotropin Unit (NU)/kg]. The analgesic effect of neurotropin was significantly inhibited not only by methysergide (100 nmol Rat , i.t.), a non-selective antagonist against serotonin (5-HT), but also MDL 72222 (30 nmol Rat , i.t.), a selective 5-HT3 antagonist, but not influenced by ketanserin (100 nmol Rat , i.t.), a 5-HT2A antagonist. The antinociceptive effect of neurotropin (200 NU Kg , i.p.) was significantly inhibited also by yohimbine (30 nmol Rat , i.t.), a noradrenergic α2 antagonist. However, the analgesic effect of neurotropin (100 and 200 NU Kg , i.p.) was not influenced by naloxone (30 nmol Rat , i.t.), an opioid antagonist. These results suggest that the mechanism of the antinociceptive effect of neurotropin is via enhancement of endogenous descending pain inhibitory pathways of the serotonergic and noradrenergic systems, especially involving 5-HT3 and noradrenergic α2 receptors in spinal dorsal horn in which these neurons terminate. No influence of opioid receptors at the spinal cord level is indicated.

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 report a case of a thymic carcinoid associated with multiple endocrine neoplasia type 1( MEN-1). A 37-year-old man was referred to our hospital for further examination of an abnormal chest shadow. A chest computed tomography (CT) showed an anterior mediastinal mass measuring 6.5 cm in diameter. A pathological diagnosis of thymic carcinoid was made from a CT-guided needle biopsy specimen. Preoperative workup including endocrinological examination revealed a pituitary adenoma and hyperparathyroidism, and MEN-1 was clinically diagnosed. We performed total parathyroidectomy with autotransplantation and thymectomy with lymph node dissection through cervical collar incision and median sternotomy. The diagnosis of MEN-1 was confirmed by the genomic analysis postoperatively. Since 25% of thymic carcinoids are MEN-1 related and 95% of MEN-1 patients develop hyperparathyroidism, it should be kept in mind that this condition can be treated by thymectomy and concurrent parathyroidectomy.

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.

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.

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 .

Exposing mice to 24 and 4 degrees C in alternate 1 hr periods in the day time and maintaining 4 degrees C at night for several days decreases the tail clamp pressure required to evoke pain behavior. This model is referred to as SART (specific alternation rhythm of temperature) stress. An extract from inflamed skin of rabbits inoculated with vaccinia virus (neurotropin) clearly normalized the hyperalgesia in this SART stress model. To clarify the mechanism of the hyperalgesia in SART mice and the mode of the antinociceptive action of neurotropin in this model, the influence of systemically administered neurotransmitter related drugs was studied. 1) Neurotropin, 5-hydroxytryptophan and L-dihydroxyphenylalanine significantly normalized the decrease in nociceptive threshold, and muscimol tended to inhibit it in nociceptive threshold in SART stressed mice. 2) Haloperidol, phenoxybenzamine, reserpine, bicuculline, scopolamine, physostigmine and naloxone alone did not influence the nociceptive threshold in SART stressed mice. 3) The antinociceptive effect of neurotropin was significantly attenuated by p-chlorophenylalanine, haloperidol and phenoxybenzamine; and it was completely inhibited by reserpine. 4) Naloxone, bicuculline, scopolamine and physostigmine had no influence on the antinociceptive effect of neurotropin. These results suggest that hypofunction mainly of the monoaminergic systems contributes to hyperalgesia in SART stressed mice and that neurotropin produces the antinociceptive effect by restoring these neural functions.

Objective Salt intake restriction is important to health maintenance in subjects tending toward excessive intake. For convenience salt intake is ordinarily estimated at health check up centers using a salt-preference questionnaire, but whether or not the questionnaire identifies excessive salt consumers is unclear. Methods Daily salt intake in 725 subjects including 452 men examined at our health-check center was estimated by a spot urine method developed by Kawasaki et al (Clin Exp Pharmacol Physiol 20:7-14, 1993). Results from the questionnaire were used to divide into salt preference and non-salt preference groups. Results Daily salt intake estimated by the spot urine method was 13.5±3.5 g in male subjects and 12.4±3.1 g in female subjects. Salt preference subjects included 42% men and 24% of women. As a daily salt intake of less than 10 g is recommended for the general population in Japan, subjects whose salt intake exceeded 10 g were considered excessive salt consumers. Among men, excessive salt consumers comprised 85% of the salt preference group and 84% of the non-salt preference group. Among women, 88% of the salt preference group and 76% of the non-salt preference group were excessive consumers. Conclusions A simple questionnaire for salt preference was not effective in identifying excessive salt consumers. Convenient, reliable methods for the estimation of salt intake, such as the spot urine method, are recommended in place of the questionaire.

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.

A 72-year-old-man with night sweats and a low-grade fever was found to have bilateral adrenal enlargement associated with incipient adrenal insufficiency. Without any intervention, these adrenal lesions regressed spontaneously, accompanied by disappearance of clinical symptoms. Seven months later, however, the lesions became enlarged and exceeded their initial size while remaining confined to the adrenals, associated with reappearance of nights sweats and overt adrenal insufficiency. Upon unilateral laparoscopic adrenalectomy, the lesion proved histopathologically to be diffuse large B cell non-Hodgkin's lymphoma (NHL). After contralateral laparoscopic adrenalectomy and adjuvant chemotherapy, the patient remains alive with no recurrence at 26 months. Treatment with bilateral adrenalectomy and chemotherapy is effective for aggressive NHL confined to bilateral adrenal glands. A transient clinical improvement without treatment was considered to be due to a spontaneous regression of NHL, although we could not confirm the histological results before the regression. Such tumor behavior showing spontaneous regression in spite of aggressive histology may also be related to the favorable outcome, even though regression was transient.

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.

Objective : To determine whether there is a seasonal variation in blood pressure in hypertensive patients whose daily lifestyle is similar in summer and in winter, and who live almost entirely indoors in a stable environmental temperature. Subjects and methods : During summer and winter, blood pressure was measured by ambulatory blood pressure monitoring in outpatients with essential hypertension, and environmental temperature was measured by electrothermometer while the patients were awake. The 24-h blood pressure data were analysed after being divided into four groups : morning, afternoon, night-time and sleeping periods. Results : We studied 25 outpatients (mean ± SD age 57 ± 12 years) who spend virtually the entire day indoors in both summer and winter. Measurements of systolic and diastolic blood pressure in the morning and night-time periods were significantly higher in winter than in summer (differences of 7.5 ± 14.7 and 4.1 ± 8.8 mmHg and 8.2 ± 14.8 and 4.5 ± 18.1 mmHg, respectively). Blood pressure measured in the afternoon and during sleeping periods did not differ significantly. No correlation was observed between the seasonal change in blood pressure in the morning and that at night. Environmental temperatures were significantly higher in the morning, afternoon and night-time periods during summer than those during winter. The differences among these periods were not statistically significant. Conclusions : There is a seasonal variation in blood pressure in the morning and night-time periods during winter in hypertensive patients who live essentially indoors in a relatively stable environmental temperature. Pressor factor(s) may differ between morning and night-time periods during winter.

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.

Experiments were conducted on 119 anesthetized and artificially ventilated rats to evaluate effects of a physiological stimulus (hemorrhage) to the sympothoadrenal system on the bronchial circulation. In the presence of a sufficient dose of a vasopressin V1-receptor antagonist, moderate (81 mmHg on average, 33 rats) or severe hypotension (69 mmHg, 28 rats) was produced by controlled hemorrhage (11 or 9 rats, respectively), or by treatment with phenoxybenzamine (0.1 mg/kg, i.v., 12 rats, or 1.0 mg/kg, 10 rats), or the highly selective alpha 1-adrenoceptor antagonist, bunazosin (0.01 mg/kg i.v., 10 rats, or 0.1 mg/kg, 9 rats). During hypotension, the intrapulmonary bronchial blood flow (microsphere method) was decreased in a dose-dependent manner in the two antagonist-treated groups. However, these decreases were only of a moderate degree compared to the severe decrease in the hemorrhage group. Although the bronchovascular resistance was not significantly changed after treatment with either antagonist, this variable was greatly elevated during severe hemorrhagic hypotension, reaching 240 +/- 51% (P less than 0.001 with either antagonist study) of its baseline level. Changes in the pulmonary arterial and left atrial pressures, plasma vasopressin concentration, and renin activity were found to be less influential on these responses in 58 rats. Overall, we concluded that the sympathoadrenal mechanism powerfully increased the resistance and decreased the blood flow of the intrapulmonary bronchial circulation.

Among patients who were found to have hypertension by office or clinic blood pressure (BP) measurement, some appear to be normotensive when studied for full 24-hour periods by ambulatory BP monitoring, indicating so-called “office” or “white-coat” hypertension. Within groups of hypertensive patients with similar office BPs, those with higher than predicted ambulatory BP have greater prevalence of target-organ damage1,2 and a significantly greater 10-year incidence of fatal and unfatal events than those with lower than predicted ambulatory BP.3 Moreover, there is some indication that reducing BP too much may exert a deleterious rather than a beneficial effect on coronary events.4 In the present study, we examined and compared the effects of the long-acting calcium antagonist nifedipine slow-release tablet (nifedipine SR) with the effects of the long-acting angiotensin converting enzyme inhibitor enalapril on office, home and ambulatory BP measurements. We studied hypertensive patients with relatively higher and relatively lower ambulatory BPs.

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.

We compared the effects of intrathecal administration of antiserum against calcitonin gene-related peptide (CGRP) between thermo- and mechano-nociceptive responses, using experimental hyperalgesic rats. An intrathecal administration of anti-CGRP antiserum, but not antiserum absorbed by synthetic CGRP, normalized either adjuvant- or carrageenin-induced hyperalgesia both in the paw radiant heat and the paw pressure tests, with little effect on non-hyperalgesic paws. These results suggest that endogenous CGRP, probably present in primary afferents, promotes both thermo- and mechano-nociceptive transmission in the spinal dorsal horn, at least in the hyperalgesic states with inflammations.

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.

Effects of calmodulin antagonists on renin release from isolated rat glomeruli were examined. The calmodulin antagonists used were N-(6-aminohexyl)-5-chloro-naphthalene-1-sulfonamide (W-7), triflupromazine and trifluoperazine. These drugs induced renin release from isolated glomeruli in a dose-dependent manner. The threshold concentration for renin release in the calcium-containing medium was 50 microM for W-7, 5 microM for triflupromazine and 2 microM for trifluoperazine respectively. The threshold concentrations were 2-5 times less in the calcium-free medium. The maximum levels of renin release by the three antagonists were similar in both calcium-containing and calcium-free media. In the absence of these antagonists, the basal rate of renin release in the calcium-free medium was markedly higher than in the calcium-containing medium. These results suggest that the calcium-calmodulin system inhibits renin release and that renin release is regulated by a mechanism different from the calcium-stimulated exocytotic mechanism by which many hormones are released.

In order to verify the contribution of right atrial pressure to atrial natriuretic polypeptides (ANP) release, we measured plasma levels of immunoreactive (ir)-ANP when graded rise of right atrial pressure was executed in anesthetized dogs. Increasing right atrial pressure (RAP) from 2.7 +/- 0.6 to 9.0 +/- 0.7 mmHg, plasma levels of ir-ANP in aorta tended to increase by 33% but not significantly (p greater than 0.05). However, when RAP was increased from 9.0 +/- 0.7 to 17.0 +/- 1.1 mmHg, ir-ANP levels in aorta were significantly (p less than 0.05) increased by 132% of control within 5 min from the start of RAP elevation. The RAP elevation produced a sustained increase in plasma levels of ir-ANP. There was a positive correlation between right atrial pressure and plasma levels of ir-ANP. The plasma levels of ir-ANP were similar between aorta and pulmonary artery. These results demonstrate that increasing atrial pressure is closely correlated with ANP release and ANP is not greatly metabolized by pulmonary circulation.