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1. Plasma sodium concentration may influence renal sodium excretion. We have examined the possibility that the fall in plasma sodium that occurs during salt restriction in man might be an important stimulus for renal sodium conservation. 2. In order to prevent the fall in plasma sodium that usually occurs during dietary salt restriction, we water restricted (200 ml/day) six normal subjects for the 2 days after the transition from 260 (high-sodium diet, day 3) to 20 mmol (low-sodium diet, days 4 and 5) sodium per day. In the control (hydrated) group water intake was held constant at 1800 ml/day. 3. Plasma sodium fell during the low-sodium diet in the hydrated group but remained constant in the dehydrated group (141.3 +/- 0.2 to 140.2 +/- 0.2 mmol/l versus 141.1 +/- 0.3 to 141.3 +/- 0.3 mmol/l). Plasma arginine vasopressin concentration was significantly higher and urine flow lower during the low-sodium diet in the dehydrated group (arginine vasopressin on day 5: hydrated group, 0.72 +/- 0.1 pmol/l; dehydrated group, 2.18 +/- 0.5 pmol/l). Weight fell by a similar amount in both groups (hydrated group, 1.23 +/- 0.17 kg; dehydrated group, 1.45 +/- 0.19 kg). 4. On the low-sodium diet there were no differences between groups in changes in plasma renin activity (hydrated group, 1.6 +/- 0.24 to 4.78 +/- 0.65 nmol angiotensin I h-1 ml-1; dehydrated group 1.57 +/- 0.18 to 5.14 +/- 0.56 nmol angiotensin I h-1 ml-1) or atrial natriuretic peptide (hydrated group, 23 +/- 2.3 to 14.7 +/- 1.6 pg/ml; dehydrated group, 26.8 +/- 3.6 to 12.7 +/- 1.3 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

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1. We have previously described a progressive antidiuresis in response to low-dose vasopressin infusion during salt restriction in man, despite stable or even declining plasma vasopressin concentration. In the present study we examine the hypothesis that renal sensitivity to the antidiuretic effect of arginine vasopressin may be enhanced by salt restriction. 2. Extremely low-dose infusions of arginine vasopressin were given to normal subjects after equilibration to high (260 mmol/day) and low (20 mmol/day) sodium intakes. 3. Salt restriction increased the antidiuretic effect of arginine vasopressin (2 fmol min-1 kg-1 arginine vasopressin increased urine osmolality from 67.8 +/- 2.6 to 196.3 +/- 35.7 mosmol/l in the high-salt study and from 268.3 +/- 49 mosmol/l in the low-salt study; P < 0.05 between sodium intakes). Glomerular filtration rate, estimated from inulin clearance, was unchanged during arginine vasopressin infusion irrespective of salt intake (high salt 116.5 +/- 9.4 to 118.9 +/- 6.4 ml/min; low salt, 135.1 +/- 9.2 to 111.2 +/- 12.4 ml/min). Renal plasma flow, estimated from para-aminohippurate clearance, fell further during infusion of 2 fmol min-1 kg-1 arginine vasopressin in the low-salt study than in the high-salt study (low salt, from 555.7 +/- 22.7 to 298.3 +/- 27.6 ml/min; high salt, from 544.5 +/- 30.2 to 452.9 +/- 28.9 ml/min; P < 0.05 between sodium intakes).(ABSTRACT TRUNCATED AT 250 WORDS)

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1. We have studied the response of six patients with cranial diabetes insipidus and six age-matched control subjects to dietary sodium restriction during constant administration of the synthetic vasopressin analogue desamino-[8-D-arginine]vasopressin. 2. Urine flow increased on the first low salt day in the normal control subjects but not in the patients with cranial diabetes insipidus. Body weight fell 1.35 kg in the control subjects but was constant in the patients with cranial diabetes insipidus. 3. Urinary sodium excretion fell at the same rate in both groups. Diurnal variation of urinary sodium excretion and creatinine clearance was present in the control subjects but not in the patients with cranial diabetes insipidus. 4. Changes in plasma sodium concentration and osmolality were similar. Plasma protein concentration increased more in the control subjects (from 69.1 +/- 1.5 to 73 +/- 1.2 versus from 71.7 +/- 1 to 73.2 +/- 1.1 milligrams). The responses of plasma atrial natriuretic peptide, plasma renin activity and salivary aldosterone concentration were similar between the two groups. Salivary aldosterone concentration levels were consistently higher in the patients with cranial diabetes insipidus. 5. We confirm that the low salt diuresis is triggered by release from the antidiuretic activity of arginine vasopressin. In the patients with cranial diabetes insipidus extracellular fluid osmoregulation appeared to be achieved by the movement of water out of and sodium into the extracellular fluid. 6. Absent posterior pituitary function and hypothalamic disturbances did not alter renal sodium conservation.(ABSTRACT TRUNCATED AT 250 WORDS)

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1. A diuresis occurs within the first 36h of salt restriction. A decline in plasma arginine vasopressin concentration may contribute to both the diuresis and antinatriuresis. 2. We have studied six normal human subjects during 36h of dietary sodium restriction. In one study subjects received an intravenous infusion of D-glucose, and in the other an infusion of arginine vasopressin (6 fmol min-1 kg-1). 3. In the D-glucose phase plasma arginine vasopressin concentration fell (1.77 +/- 0.34 to 1.02 +/- 0.13 pg/ml), urine flow increased (67.9 +/- 11.5 to 89.8 +/- 17.1 ml/h), haemoconcentration occurred (packed cell volume 40.8 +/- 0.3 to 42.8 +/- 0.5%, protein concentration 71.6 +/- 0.5 to 74.5 +/- 0.6 g/l), plasma sodium concentration fell (140 +/- 0.2 to 138 +/- 0.2 mmol/l) and plasma renin activity increased (1600 +/- 153 to 3700 +/- 356 pg of angiotensin I h-1 ml-1). 4. In the arginine vasopressin phase plasma arginine vasopressin concentration remained constant (1.5 +/- 0.13 to 1.34 +/- 0.11 pg/ml), the diuresis was reversed (65.7 +/- 9.9 to 52.1 +/- 8.9 ml/h), plasma sodium concentration fell further (139.8 +/- 0.4 to 136.1 +/- 0.4 mmol/l), the rise in plasma renin activity was reduced (arginine vasopressin 2552 +/- 292; D-glucose, 3700 +/- 356 pg of angiotensin I h-1 ml-1) and creatinine clearance was lower in the last 12h of salt restriction (arginine vasopressin, 96.1 +/- 6.9; D-glucose 116.5 +/- 6.8 ml/min). Renal sodium excretion was unaffected by arginine vasopressin infusion. 5. We conclude that the fall in plasma arginine vasopressin concentration during dietary salt restriction, whilst not affecting renal sodium excretion, may be important in the regulation of plasma sodium concentration, plasma renin activity and glomerular filtration.

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BACKGROUND: An earlier prospective study reported an association between high levels of plasma renin activity (as measured by the renin-sodium profile) and the incidence of myocardial infarction in patients with hypertension. We have investigated the relation between plasma renin activity and ischemic heart disease in the Northwick Park Heart Study. METHODS: The study included 803 white men 40 to 64 years of age selected from industrial workers in London. Plasma renin activity and established risk factors for ischemic heart disease were measured at entry, which was between 1972 and 1978. Ascertainment of the primary clinical end points of fatal or nonfatal myocardial infarction and sudden death from coronary causes was carried out until the end of 1991. RESULTS: In an analysis of the 86 first coronary events, we found an independent relation between higher systolic blood pressure and coronary end points (relative risk per 1 SD increase in blood pressure, 1.47; 95 percent confidence interval, 1.16 to 1.85; P < 0.001), but no relation between plasma renin activity and coronary end points (relative risk per 1 SD increase in the level of plasma renin activity, 1.04; 95 percent confidence interval, 0.84 to 1.30). In the 242 men who had hypertension of a degree similar to that of the subjects in the earlier prospective study of the renin profile, and in whom 44 of the 86 coronary events occurred, the relative risk of those in the highest as compared with the lowest third for plasma renin activity was 1.26 (95 percent confidence interval, 0.63 to 2.56). CONCLUSIONS: Our results suggest that there is no association between plasma renin activity and myocardial infarction or sudden death from coronary causes, at least in normotensive men.

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1. The effects of change from a high to low sodium diet upon renal sodium and water excretion and hormone responses were studied in patients with dissociated sympathetic control (DS, tetraplegic) and controls with sympathetic control largely intact (IS, paraplegic). 2. Total and fractional urinary sodium excretion fell in response to sodium restriction in both groups, but the fall in fractional sodium excretion was greater in the DS group compared with the IS group (DS, 1.34 +/- 0.12 to 0.42 +/- 0.05%; IS, 0.96 +/- 0.08 to 0.52 +/- 0.06%). 3. Supine mean arterial pressure fell during the low salt period in the DS group (80.2 +/- 2.7 to 74.4 +/- 2.3 mmHg) but was unaffected by salt restriction in the IS group (101 +/- 2.3 to 98.8 +/- 2.7 mmHg). In the DS group, creatinine clearance remained constant throughout the low salt period (103.7 +/- 7.9 to 98.3 +/- 9.7 ml min-1), but fell during salt restriction in the IS group (101.4 +/- 8.5 to 83.2 +/- 5 ml min-1). 4. Plasma renin activity was lower during salt loading in DS subjects but increased more rapidly and to higher levels in response to salt restriction (DS, 1021 +/- 142 to 4439 +/- 355; IS, 1765 +/- 269 to 3683 +/- 465 pg angiotensin I ml-1 h-1). Plasma atrial natriuretic peptide concentration was higher in the DS group during salt loading and salt restriction (DS, 37.6 +/- 5.6 to 22 +/- 3.8; IS, 20.2 +/- 2.3 to 11 +/- 1.6 pg ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)

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After the development of blood pressure measurements in humans, the association of high blood pressure with renal disease was established. Injection of extracts of various organs in an attempt to replace their secretions was common in the 19th century, and it was therefore natural for Tigerstedt and Bergman to investigate the effects of renal extracts. In this way, they discovered renin. This paper covers the methods by which its mode of action was uncovered, as well as its relation to renal ischemia and hypertension.

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The contribution of neurogenic mechanisms in maintaining hypertension was investigated in 13 patients with unilateral renal artery stenosis (twelve with normal, one with grossly elevated plasma renin levels) by determining the haemodynamic and hormonal responses to the centrally acting sympatholytic agent, clonidine. The same patients were studied after captopril to determine the dependency of their blood pressure on the direct peripheral effects of angiotensin-II. Sixteen patients with essential hypertension (normal plasma renin) were additionally studied after clonidine. After clonidine, blood pressure fell markedly in patients with renal artery stenosis (17 +/- 3%) and essential hypertension (18 +/- 2%). In both groups, clonidine lowered cardiac output by a reduction in stroke volume and heart rate; forearm vascular resistance was unchanged but digital skin vascular resistance fell. Plasma noradrenaline levels were normal in both groups and fell after clonidine; plasma renin activity and aldosterone levels were unchanged. After captopril, blood pressure fell minimally (5 +/- 3%) in renal artery stenosis patients; cardiac output fell and forearm and digital skin vascular resistance were unchanged. Plasma renin activity rose, plasma aldosterone fell and plasma noradrenaline was unchanged after captopril. In the patient with grossly elevated renin levels, blood pressure fell minimally (6%) after clonidine, but unlike others fell profoundly (37%) after captopril. We conclude that, in the majority of our renal artery stenosis patients, despite the elevated blood pressure, sympathetic nervous activity was not reduced. Central neurogenic mechanisms appear to play an important role in maintaining raised blood pressure. In the same patients the peripheral effects of angiotensin-II did not maintain vascular tone or hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

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BACKGROUND: Clonidine, a partial presynaptic and postsynaptic alpha-adrenoceptor agonist, has been shown to lower blood pressure in normal subjects but not in tetraplegics; however, the mechanisms of this action have not been elucidated. METHODS AND RESULTS: The hemodynamic and hormonal basis of the hypotensive action of clonidine was investigated in tetraplegics with complete cervical spinal cord transection and preganglionic sympathetic denervation, in patients with unilateral brachial plexus injury and postganglionic sympathetic denervation, and in normal subjects. In normal subjects, the fall in blood pressure after clonidine infusion was accompanied by a reduction in cardiac output that was predominantly due to a fall in stroke volume and in heart rate. The lack of fall in blood pressure, cardiac output, and stroke volume in tetraplegics indicates that these effects are exerted at a supraspinal level and require intact descending sympathetic pathways. After clonidine infusion, digital skin vasodilatation occurred in normal subjects, in the innervated but not the denervated limb of patients with unilateral brachial plexus injury, and in tetraplegics, indicating that this response is due to the central sympatholytic effect of clonidine. Plasma norepinephrine was much lower in tetraplegics compared with normal subjects, and after clonidine infusion, it fell substantially in normal subjects alone. Plasma renin activity did not change. Bladder stimulation in tetraplegics resulted in a rise in blood pressure and vasoconstriction in digital skin vessels. The inability of clonidine to significantly reduce or abolish the pressor and digital vasoconstrictor responses after bladder stimulation in tetraplegics indicates that clonidine does not exert a major effect on spinal preganglionic neurons or peripheral presynaptic alpha 2-adrenoceptors. CONCLUSIONS: Therefore, clonidine is a suitable drug for use in analyzing the central supraspinal levels of control in varying circulatory disorders, such as hypertension and postural hypotension.

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Patients with ileostomies show an early diuresis when sodium restricted; this, together with an obligatory ileal sodium loss, predisposes them to severe salt and water depletion. The role of arginine vasopressin in this circumstance and whether it is natriuretic, or antinatriuretic, is unclear. There is also controversy over its likely effect on small bowel fluid reabsorption. We have examined the effect of the non-pressor (V2) synthetic vasopressin analogue 1-deamino-8-D-arginine (desmopressin) on renal and ileal sodium and water excretion in ileostomy patients during acute adaptation to a low sodium diet. Patients were studied on two separate occasions (nonrandomised) with and without the administration of desmopressin (0.75 micrograms intramuscular, three times a day). In eight subjects without desmopressin there was pronounced diuresis on the first low sodium day, associated with a fall in renal sodium excretion and no change in ileal output or composition. In five (of the original) subjects with desmopressin there was pronounced antidiuresis, no change in renal sodium excretion, and no change in ileal output or composition. In both studies rises in plasma renin activity and salivary aldosterone concentration lagged behind the early decline in renal sodium excretion. We have confirmed the phenomenon of 'low sodium' diuresis after sodium restriction in ileostomy patients and shown that it can be prevented by desmopressin. Desmopressin has no direct or indirect effect on renal sodium excretion or ileal fluid and electrolyte loss in humans.

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1. The fall in renal sodium excretion after dietary sodium restriction is prompt and reproducible. The importance of increased aldosterone secretion during the early phase (within 48 h) of this response is unclear. Using two indirect measures of aldosterone secretion (in urine and saliva), we have tried to relate changes in excretion and concentration of this hormone to renal sodium excretion during the abrupt transition from a normal (approximately 150 mmol/day) or high (260 mmol/day) to a low (5-25 mmol/day) sodium intake in 11 and seven male volunteers, respectively. 2. All subjects showed reduced renal sodium excretion within 36 h of dietary restriction, but the times at which increases in renal aldosterone excretion, saliva aldosterone concentration and plasma renin activity became statistically significant varied widely (8-72 h, 2.5- greater than 62.5 h and less than 4- greater than 38 h for renal aldosterone secretion, saliva aldosterone concentration and plasma renin activity, respectively). Circadian fluctuations in saliva aldosterone concentration were apparent and increased in amplitude during sodium restriction. 3. Urine flow rate tended to increase on the first day of sodium restriction and this reached statistical significance in the group initially on a high sodium intake (64.0 +/- 8.8 to 84.3 +/- 11.2 ml/h, P less than 0.01); although the pattern of urine flow did correlate with plasma arginine vasopressin concentration (r = -0.49, P less than 0.01), there was no significant decrease in mean plasma arginine vasopressin concentration [1.15 (0.92-1.44) to 0.90 (0.72-1.12) pmol/l, P = 0.08; geometric mean and 95% confidence limits].(ABSTRACT TRUNCATED AT 250 WORDS)

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OBJECTIVE: To demonstrate the magnitude, timing, and cause of changes in blood pressure that occur in migrants from a low blood pressure population on moving to an urban area. DESIGN: A controlled longitudinal observational study of migrants as soon after migration as possible and follow up at three, six, 12, 18, and 24 months after migration. A cohort of controls living in a rural area who were matched for age, sex, and locality were also observed at the same periods. SETTING: 35 Villages on the northern shores of Lake Victoria in western Kenya and Nairobi. PARTICIPANTS: 325 Members of the Luo tribe aged 15 to 34 years who had migrated to Nairobi and 267 controls living in villages. The numbers of both groups reduced during follow up such that only 63 migrants and 143 controls were followed up for two years. MAIN OUTCOME MEASURES: A medical questionnaire and three 24 hour diet histories were completed by migrants and controls. Height, weight, pulse, and blood pressure were measured. Three 12 hour overnight urine samples were collected from all participants and analysed for sodium, potassium, and creatinine concentrations. RESULTS: The mean systolic blood pressure of migrants was significantly higher than that of controls throughout the study, and the distribution of blood pressure was shifted to the right compared with controls. The mean diastolic blood pressure of the two groups diverged over time. Blood pressure differences were not due to selective migration. The migrants' mean urinary sodium:potassium ratio was higher than that of controls (p less than 0.001) throughout, and weight and pulse rate were also higher among migrants, although differences diminished with time. CONCLUSIONS: Urinary sodium:potassium ratio, pulse rate, and weight are important predictors of increased blood pressure among migrants from a low blood pressure community and may also be implicated in the initiation of essential hypertension.

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1. To investigate the contribution of sedation to the cardiovascular effects induced by clonidine, we studied patients with essential hypertension on two separate occasions when similar levels of sedation were induced by clonidine and nitrazepam. 2. After clonidine, there was a fall in blood pressure, heart rate, digital skin vascular resistance and plasma noradrenaline which is consistent with its ability to reduce sympathetic outflow. Dissociation of the circulatory/neurohormonal and sedative responses after clonidine indicated that sedation alone is not an important factor in the blood pressure lowering effect of clonidine. 3. The absence of a fall in blood pressure, heart rate, digital skin vascular resistance and plasma noradrenaline after nitrazepam further suggest that sedation did not influence the hypotensive response in essential hypertension.

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We have determined the haemodynamic responses to a balanced liquid meal in eight normal subjects, before and after administration of the somatostatin analogue, Octreotide (SMS 201-995), which inhibits the release of gastrointestinal peptides. In the absence of Octreotide ingestion of the meal caused a marked increase in superior mesenteric artery (SMA) blood flow. Blood pressure was maintained, presumably by a compensatory rise in cardiac output and forearm vascular resistance. After Octreotide there was a fall in SMA blood flow alone, with no further changes after food ingestion. We conclude that Octreotide prevents the haemodynamic changes following food ingestion, probably by inhibiting the release of those gastrointestinal peptides that induce splanchnic vasodilatation.

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Human fetal lung homogenates contain an inactive form of renin which may be revealed by trypsin treatment. When activated, this form of renin has some biochemical similarities with fetal kidney renin: the pH optimum of fetal lung renin is approximately 6.5; it is bound by Affigel Blue affinity chromatography resin; and is inhibited by a monoclonal antibody (R-3-36-16) raised to human kidney renin. Inactive renin, partially-purified from both fetal kidney and lung, differs from this in that the renal form is of low-molecular weight (LMW, 45,000 daltons), whereas that from fetal lung is of high molecular weight (HMW, 58,000 daltons). Using a sensitive alkaline phosphatase-anti-alkaline phosphatase (APAAP) procedure with a polyclonal anti-renin antibody (R-15), immunoreactive renin in fetal lung was found in vessels in mesenchyme between airways. The pattern of staining was distributed similarly to Factor VIII-related antigen, suggesting localization in endothelial cells.

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We have studied the haemodynamic, hormonal and urinary effects of postural change in 6 tetraplegic patients, 6 paraplegic patients and 6 normal subjects. Measurements of blood pressure and heart rate, plasma renin activity, plasma aldosterone, urine volume and electrolyte excretion were made for 60 minutes while sitting and 60 minutes while recumbent. In tetraplegics the blood pressure was lower when sitting and rose during recumbency, unlike paraplegics and normal subjects. Plasma renin activity and aldosterone were higher in tetraplegics when sitting compared to normal subjects and did not fall during recumbency. Urine output increased significantly after recumbency in tetraplegics, but not in paraplegics or normal subjects. Both urinary sodium and potassium excretion were lower in tetraplegics and higher in paraplegics compared to normal subjects when sitting. In paraplegics the fall in both sodium and potassium excretion did not appear to be related to change in posture. Our observations indicate that recumbency induces a diuresis in tetraplegics but not in paraplegics or in normal subjects. The diuresis in tetraplegics may be related to the accompanying haemodynamic and hormonal changes induced by recumbency.

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We studied the haemodynamic effects of clonidine (2 micrograms/kg/iv) in 7 tetraplegics and 7 normal subjects. Measurements of blood pressure, stroke volume, cardiac output and digital (finger) skin blood flow were made before and after clonidine for 60 minutes. Blood pressure, stroke volume and cardiac output did not fall in tetraplegics, unlike normals. Resting digital skin blood flow was higher in tetraplegics and fell after clonidine. In normal subjects however, an increase in digital skin blood flow occurred after clonidine. The pressor and digital vasoconstrictor responses to bladder stimulation were attenuated after clonidine. The inability of clonidine to induce a fall in blood pressure, stroke volume, cardiac output and cause peripheral vasodilation in tetraplegics is consistent with its central sympatholytic effects. Attenuation of the responses to bladder stimulation suggest an effect on spinal sympathetic neurones.

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1. The effect of intravenous vasoactive intestinal peptide (VIP, 6 pmol/kg per min) on renal function in six patients with cirrhosis of the liver was examined. 2. VIP caused generalized vasodilation and increased plasma renin activity, but diminished the glomerular filtration rate by about one third. 3. The excretion of water, sodium, potassium and calcium also fell significantly. 4. These results differ from our findings in normal man in whom VIP diminished water and electrolyte secretion largely by increasing tubular reabsorption. 5. It is concluded that the elevated VIP levels present in patients with severe liver disease may affect renal function, but that the presence of liver disease may affect renal responses to VIP.

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The authors have used a sensitive alkaline phosphatase-anti-alkaline-phosphatase immunohistochemical method to examine 28 human pulmonary carcinomas for the presence of renin. Immunoreactive renin was found in 23 (82%) cases. Specific staining was always associated with small vessels in the stroma of the tumor or in adjacent areas of inflamed fibrous tissue. Within vessels, renin was localized in the cytoplasm of medial cells. Adenocarcinoma exhibited the most consistent staining (11/12 cases), and this appeared to be independent of the degree of tumor differentiation. Immunoreactive renin was also detected in squamous cell (7/8 cases), undifferentiated large cell (4/4 cases), and small cell undifferentiated carcinoma (1/1 cases), but the number of vessels and intensity of staining were usually less than seen in adenocarcinoma. Staining was not found in the bronchioloalveolar variant of adenocarcinoma (0/3 cases). By means of immunoaffinity chromatography with monoclonal antibodies (MAbs) raised to kidney renin, both active and inactive renin were extracted from homogenates of surgical specimens. The molecular weight of both forms of renin was approximately 59,000 daltons.

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