Search

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)

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)

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)

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.

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.

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)

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.

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)

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.

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.

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)

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.

Sixteen hypertensive patients received pindolol (10-45 mg/day); mean +/- SD, 28.75 +/- 15.22) for 3-8 weeks in a placebo-controlled, single-blind, crossover study. Supine and standing blood pressures (BP) were lowered, whereas effective renal plasma flow and glomerular filtration rates (estimated from the clearances of Hippuran and EDTA during oral water loading) did not change consistently. "Blood volume" (calculated from 125I-human serum albumin space and microhaematocrit) increased, with a corresponding reduction in serum albumin but without a change in body weight or "total body water" (T2O space). The results suggest a transfer of water from the interstitial to the intravascular compartment. This was supported by estimates of "extracellular fluid volume" (EDTA space) and "interstitial volume" (EDTA) minus human serum albumin spaces) in 3 subjects. The changes produced in "blood volume" correlated with those in BP. Plasma levels of noradrenaline, renin activity, and aldosterone were reduced, as was renal aldosterone excretion. There was no correlation between the changes produced by pindolol in BP and these hormone levels. Pindolol treatment reduced serum calcium concentration. There was a strong positive correlation between changes in BP and serum calcium and renal calcium excretion.

1 The effect of pindolol administered to twenty-six patients with hypertension of unknown origin was compared with respect to blood pressure and plasma renin activity change after increase of the dose over a period of 6 weeks. 2 There was no clear correlation between the fall of plasma renin activity, which in some patients was very marked, and the fall in blood pressure. Some patients with a fall in plasma renin activity did not drop their pressure. Conversely, some with a fall of pressure did not drop their plasma renin activity. 3 The addition of hydrochlorothiazide to the pindolol finally caused further lowering of the blood pressure in all but one patient and the plasma renin activity rose in all but two patinets. There was no clear correlation between change in plasma renin activity and the effect on blood pressure.

Changes in blood pressure (BP) and associated factors which occur on migration from a rural to an urban environment are under observation in a longitudinal study. Blood pressures, heart rate (HR), urinary electrolytes, sociological and anthropometric data are recorded at 0, 3, 6, 12, 18 and 24 months following migration and compared with a cohort of age and sex-matched rural based controls. Data from the first 6 months' follow-up reveal that the migrants' BPs are higher and tend to rise compared with controls, in whom BP falls progressively with time. Changes in body weight and dietary electrolytes appear to explain some of the BP differences, while differences in pulse rates between groups suggest that a further mechanism operative through the autonomic nervous system is responsible for some of the elevation of systolic BP shown amongst migrants, particularly on arrival in the urban area.

The history of the development of ideas on the cause of renal hypertension is first discussed. Growth of knowledge of renin and angiotensin from 1898 to the present is shown to depend upon better and more specific assays for each part of the system, which has enabled knowledge of the role of the renin-angiotensin system in various forms of hypertension to be assessed accurately. The difficulties of assessing varying levels in relation to their biological effect is stressed and the importance of the use of blockers of both renin and angiotensin is shown to mark a very large advance in the study of various forms of renal hypertension where there is a complicated relationship, still ill-defined, between renin, angiotensin, sodium and body fluid volumes.

1. A renin-inhibitory material has been partially purified from soluble extracts of the pig kidney cortex by ammonium sulphate precipitation and diethylaminoethylcellulose (DEAE) chromatography and its properties studied. 2. It displayed competitive type kinetics. It did not inhibit cathepsin D, carboxypeptidase A, pancreatic kallikrein or trypsin. 3. Renins from dogs, rabbit and rat were inhibited, but not those from sheep or man, when assayed with pig angiotensinogen. 4. The material was inactivated by treatment with trypsin, N-ethylmaleimide or p-chloromercuribenzoate. 5. Renin-inhibitory activity was not found in plasma from peripheral blood of pigs. 6. It is concluded that the function of the renin inhibitor in the renal cortex of the pig may be restricted to the intrarenal environment.

Of 409 patients attending a clinic for control of hypertension, 74 (18%) were found to have haematuria, and all those with haematuria had significant renal impairment. The association of raised serum IgA levels and HLA BW35 in these patients suggests that some have the adult form of the IgA/C3 disease described in children.

1. The electrolyte and water composition of urine and ileal fluid was studied in six patients with ileostomies during dietary sodium deprivation and at the same time measurements were made of plasma renin activity, plasma aldosterone concentration, renal aldosterone excretion and plasma arginine vasopressin concentration. 2. In each subject there was a reduction in renal sodium excretion within 24 h of sodium deprivation. Significant rises in plasma renin activity, plasma aldosterone concentration and renal aldosterone excretion occurred by day 2 of sodium deprivation. 3. There was only modest conservation of sodium by the ileum during sodium deprivation, but ileal potassium concentration rose progressively. There were significant associations between ileal-fluid potassium concentration and plasma renin activity or renal aldosterone excretion. 4. Under the conditions of the experiment a diuresis was observed in each subject during dietary sodium deprivation. This did not appear to depend on changes in plasma arginine vasopressin concentration.

1. The epidemiological characteristics of plasma renin activity (PRA) were established in 1999 members of occupational groups in North and West London. 2. The main finding was that PRA was inversely associated with systolic blood pressure in men, the percentage fall in PRA (on a log scale) being 8.4% for each increase of one standard deviation in systolic blood pressure. There was a less obvious inverse relationship in women. 3. However, blood pressure accounted for less than 1% of the variance in PRA. 4. Mean PRA in both smokers and ex-smokers was about 20% higher than in non-smokers. 5. PRA fell with increasing age, was lower in women than in men and considerably lower in blacks (of either sex) than whites. 6. PRA was lower in the first quarter of the menstrual cycle than in the rest of the cycle. 7. Haemoglobin, blood cholesterol, leucocyte count and Factor VIII were positively correlated with PRA. 8. PRA was lower in men with diagnosed hypertension than in those without; there was no significant difference in the women. 9. PRA was lower in those who had had myocardial infarcts in the past than in those who had not. 10. The data as a whole suggest that it may be low, not high, levels of PRA which are associated with increased risks of cardiovascular disease in which hypertension is a predisposing factor. 11. The explanation may be a homoeostatic fall in PRA in response to a rise in blood pressure rather than a major causal role for PRA in the pathogenesis of essential hypertension and target-organ damage.

Five normal adults defaecated within 2 1/2 hours of receiving neurotensin 13.5 pmol kg-1 min-1 for 30 min, whereas none did so after control infusions, in a double-blind study. Neurotensin caused borborygmi and production of stools which resembled the normal contents of the proximal and distal colon in terms of consistency and electrolyte content. This evidence suggests that neurotensin had a major effect on propulsive colonic motility. Blood neurotensin concentrations during infusion were about three times higher than normal postprandial concentrations, but plasma neurotensin is raised in some diseases associated with diarrhoea.

The mechanism of alteration in renal sodium excretion in response to dietary changes is complex and poorly understood. A gut 'sensor' might exist which regulates the renal response and this may involve one or more of the now ubiquitous gastrointestinal peptides. Several of these gut peptides, including neurotensin, have been found within the kidney. Plasma levels of neurotensin, which is both a circulating hormone and putative neurotransmitter, rise promptly on feeding. When infused into the conscious rabbit, neurotensin produces a dose-related fall in renal sodium excretion.

1. The role of the sympathetic nervous system in the release of renin during head-up tilt has been studied in five normal subjects and in four tetraplegic patients with cervical spinal-cord transection above the sympathetic outflow. Blood pressure, heart rate and concentrations of plasma noradrenaline, plasma adrenaline and plasma renin activity were measured during head-up tilt to 45 degrees before and after acute beta-adrenoreceptor blockade with intravenous propranolol. 2. In the normal subjects there were minimal changes in blood pressure during head-up tilt and there was a rise in both plasma noradrenaline concentration and plasma renin activity. After propranolol values of plasma renin activity at rest fell with little change occurring during head-up tilt. 3. In the tetraplegic patients there was a substantial fall in blood pressure during head-up tilt. Concentrations of plasma noradrenaline and adrenaline did not change but there was a marked increase in plasma renin activity. Values of plasma renin activity both at rest and during head-up tilt were unaffected by propranolol. 4. We conclude that in tetraplegic patients renin release during head-up tilt may occur independently of sympathetic nervous activity and is probably largely dependent on activation of renal vascular receptors.

The effects of 300 micrograms oral clonidine were studied in 15 hypertensive patients with unilateral renal involvement -nine had renal artery stenosis and six renal parenchymal disease. After clonidine blood pressure fell substantially in both groups, with the maximum fall in the fourth hour and effects persisting after 6 h. Levels of plasma renin activity were considerably higher in the renal artery stenosis patients and remained unchanged during the study; there was a progressive fall in levels in each of the patients with renal parenchymal disease. Plasma noradrenaline levels fell in both groups. Clonidine therefore lowers blood pressure in patients with unilateral renal artery stenosis and renal parenchymal disease. The known pharmacological effects of clonidine would thus favour either an increase or an inappropriate maintenance of central pressor activity as a contributory factor to the hypertension in both groups. The central mechanisms raising blood pressure may result not only from high angiotensin II levels but to other less well defined effects, from an ischaemic or diseased kidney. The lack of fall of plasma renin activity in the renal artery stenosis patients probably indicates the greater influence of ischaemia and renal baroreceptor stimulation over sympathetically mediated renin release.

1. The subcellular distribution of low-molecular-weight and high-molecular weight forms of pig renin has been investigated. 2. Renin, in aqueous extracts of a 'renin granular fraction' prepared by differential centrifugation, after gel filtration on Sephadex G-100 displayed an apparent molecular weight of 40 000 and was not activated by acidification to pH 2.8. 3. Renin in the soluble fraction separated on Sephadex G-100 at neutral pH displayed a main peak of activity with an apparent molecular weight of 40 000. When eluates were acidified to pH 2.8 (2 degrees C, 60 min) a marked increase in renin activity was observed in the region corresponding to an apparent molecular weight of 50 000. 4. A renin inhibitory material was isolated from the soluble fraction by DEAE chromatography. This material displayed an apparent molecular weight of 50 000 and it was destroyed by acidification to pH 2.8. 5. The presence of the proteolytic inhibitor N-ethylmaleimide yielded an apparently high-molecular-weight form of renin (60 000--70 000) from the soluble fraction, but this was not found in the granular fraction. 6. We conclude that pig renal renin is stored within membrane-bounded subcellular organelles as the low-molecular-weight form. High-molecular-weight renin and renin inhibitory activity are localized to the cortical soluble fraction. In addition, the soluble fraction contains a material which in the presence of N-ethylmaleimide results in the formation of an apparently high-molecular-weight renin.

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.

1 The effect of calcium on the inhibition of renin secretion by biologically active angiotensin was investigated in the isolated rat kidney perfused with Krebs-Ringer saline.2 In the presence of calcium (3.7 mM), asp(NH(2))'-angiotensin II suppressed both basal and isoprenaline-stimulated renin secretion. Renal perfusion pressure, which was increased by the infusion of angiotensin, returned to control levels when isoprenaline was added.3 When the calcium concentration was reduced to 0.32 mM, the vasoconstriction produced by angiotensin was abolished although the inhibitory effect on renin secretion was still evident.4 In the absence of calcium, angiotensin no longer suppressed basal renin secretion and a prompt increase in renin secretion occurred when isoprenaline was added.5 The higher basal renin levels which were observed in calcium-free perfusions, suggest the existence of an intrarenal calcium-dependent mechanism that regulates basal renin secretion.6 These observations indicate that the inhibitory effect of biologically active angiotensin, on basal and isoprenaline-stimulated renin secretion, is functionally related to the contractor response by its dependence on calcium. The recognition that the renin-producing cells are modified smooth muscle cells supports this association

Renin release is believed to depend more on vasodilatation in the afferent arteriole than on any other factor. This allows for opposing effects of vasoconstriction and vasodilatation produced by sympathetic nerve stimulation by drugs or by autoregulation, to be interpreted in relation to the study of stretch of the afferent arteriole. This reduces but does not remove the necessity for alternate control through the macula densa. A final common pathway for all these stimuli is suggested through alterations in net calcium flux in the juxtaglomerular cell where increased intracellular calcium inhibits, and decreased intracellular calcium increases, renin release.

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.

A longitudinal study of the effects of migration on blood pressure and related factors is being carried out in members of a black Kenyan population who migrate from a traditional rural community to an urban environment. Data on the first 139 migrants (78 male, 61 female) and 204 control non-migrants (126 male, 78 female) who have been followed up for a period of 6 months are presented. Blood pressure changes rapidly on migration (within the first 2 months); thereafter trends between migrants and controls differ. Significant differences in systolic pressure between migrants and controls are found at all examinations during the 6 month follow-up in both sexes. Diastolic pressure falls in controls but rises in migrants, the greatest difference being seen at the 6 month examination. Migration is associated with a marked increase in dietary sodium and a fall in potassium demonstrated by measurements of urinary electrolyte excretion in 3 X 12 h or 3 X 24 h urine collections. Analysis of covariance shows that the blood pressure differences between migrants and controls are partly explained by urinary sodium/potassium ratios and in some instances by body weight.

Six healthy males received vasoactive intestinal polypeptide (VIP; 6 pmol kg-1 min-1) by intravenous infusion for 90 min, with 60 min control periods before and after. Plasma VIP levels rose by about 100 pmol l-1 during the infusion. VIP produced changes in heart rate and blood pressure consistent with generalized vasodilatation, but there were no significant changes in effective renal plasma flow or glomerular filtration rate. Both plasma solids and haematocrit rose by about 5%, suggesting that haemoconcentration had occurred during VIP infusion. Urine flow fell to about a third, and the fractional excretion of sodium, potassium, chloride and calcium fell to between half and two-thirds of control values. Fractional excretion of phosphate did not fall significantly. Plasma renin activity rose about 3-fold during VIP infusion.

The storage, synthesis, release, measurement, carriage, action and blockade of the hormones of the renin-angiotensin system are considered, with emphasis given to the effects of intrarenal vasodilatation and vasoconstriction on renin release. The concept that variation of calcium flux in the juxtaglomerular cell is the possible final step in renin release is considered. Changing views on the main site of action of angiotensin are examined, particularly in control of the cardiovascular system and of drinking behavior through a site of action in the brain. The role that blockade of various parts of the renin-angiotensin system has played in elucidating the mechanism of action of the system is discussed. The need to consider specificity of blockade in such research is emphasized. Modification of the action of angiotensin by possible initiation of a chemical cascade involving the release of other active substances is discussed. Finally, the major functions of the renin-angiotensin system in the control of blood pressure, of sodium and water balance, and of intrarenal events, are summarized.

115 factory workers (62 white, 53 black) were studied with measurements of blood pressure, plasma noradrenaline concentration, and plasma renin activity. Blood pressure was higher in blacks than in whites. There were no ethnic differences in plasma noradrenaline, which increased with age, but was not related to blood pressure. Mean plasma renin activity was 55% lower in blacks than whites and this difference was not related to differences in sodium intake. There were no associations between renin and noradrenaline, or between renin and blood pressure.

Pentagastrin and cholecystokinin octapeptide (CCK8) were infused i.v. at three different doses in two sets of 4 conscious rabbits following a repeated measurements design (130, 1,300 and 13,000 pmol kg-1 min-1 pentagastrin; 5, 50 and 450 pmol kg-1 min-1 CCK8). In man, two different doses of pentagastrin (13 and 65 pmol kg-1 min-1) were infused in two groups of 6 subjects, and CCK8 (2 pmol kg-1 min-1) in a third group. According to published human postprandial levels, plasma CCK8-like immunoreactivity concentrations were supraphysiological at all doses infused. In the rabbit, pentagastrin produced a dose-related fall in urine flow and free water clearance, but no significant change in systemic and renal haemodynamics, electrolyte excretion and measured plasma constituents; however, in human subjects, pentagastrin increased renal sodium excretion and reduced potassium excretion but did not change glomerular filtration rate. In the rabbit, CCK8 produced a dose-related fall in plasma renin activity, plasma calcium concentration and mean arterial blood pressure; dose-dependent increases in effective renal plasma flow, glomerular filtration rate and renal sodium excretion. In man, changes in sodium and potassium excretion similar to pentagastrin were observed; there were no significant changes in plasma renin activity, plasma calcium concentration, blood pressure, effective renal plasma flow or glomerular filtration rate. The pharmacological renal effects of pentagastrin in conscious water-loaded rabbits resemble vasopressin. In contrast, CCK8's most striking effect was vasodilatation and was unusual in inhibiting rather than stimulating renin release. In man the net changes in urine composition found during infusion of these peptides are similar to those produced by the potassium-sparing diuretics, amiloride and triamterene. However the generally weak renal effects observed, even at pharmacological doses, indicate that these peptides are unlikely to influence renal function under normal physiological conditions.

1. An investigation was undertaken of the role of adrenergic influences on the transient change in colonic potential difference (p.d.) induced by handling in the rabbit. 2. P.d. was increased from 9-5 +/- 0-5 to 27-05 +/- 1-94 mV during a 2 hr period of handling and wrapping. Atropine and alpha-adrenergic block during this 2 hr period did not alter the magnitude of the response and the response in adrenalectomized animals was not significantly different from that of normal animals. 3. 'Total' adrenergic block and selective beta-adrenergic block abolished the change in p.d. with handling and infusion of an alpha-receptor agonist during the 2 hr period significantly reduced the response. 4. The changes in colonic p.d. with handling were greatly increased by the infusion of a beta-receptor agonist during the 2 hr test period. 5. The results indicate that the change in colonic p.d. with handling is a direct effect of the autonomic nervous system mediated via beta-receptors and that the changes were not related to the effects of circulating catecholamines or to changes in aldosterone production.

A relationship between salt intake and blood pressure has been described in cross-sectional studies of several populations. However, serious methodological problems in many studies could have resulted in erroneous results. In the present studies, the blood pressure profiles of a Kenyan tribe have been shown to differ according to environment, being lower in rural and higher in urban communities. Although several factors could explain the observed blood pressure differences, dietary factors, including sodium and potassium intake, could be important determinants of the observed differences. A within-population study of 1,737 rural male subjects was carried out in which it was found that systolic and diastolic pressures correlated positively with urinary sodium/potassium ratios. In this rural group, within subject day-to-day variations in dietary electrolytes are small, as indicated from multiple urinary collections, and are less than those observed in Western societies. We have demonstrated in this rural population that causal samples of urine correlated well with average sodium and potassium excretion over a 7-day period. Preliminary results are reported of a longitudinal study of migrants from a low to a high blood pressure environment and a nonmigrant population. The blood pressure rise consequent to migration was related independently to changes in body weight and urinary electrolytes. The implications of these observations for active intervention studies are discussed.

1. The influence of cyclic adenosine 3',5'-monophosphate (cyclic AMP), cylic guanosine 3',5'-monophosphate (cyclic GMP) and theophylline on renin secretion was examined in the isolated kidney of the rat perfused with Krebs dextran solution. 2. Neither cyclic AMP (10(-6) to 10(-4) M) nor dibytyryl cyclic AMP (10(-5) M) produced an increase in renin secretion. 3. Cyclic GMP and 8 Br-cyclic GMP caused a small rise in renin secretion in some experiments but this effect was independent of the dose and its physiological significance is uncertain. 4. Theophylline (10(-6) to 10(14) M) caused a significant elevation in renin secretion which was not blocked by (+)-propranolol. Theophylline with cyclic AMP or cyclic GMP did not produce an amplified effect. 5. Despite previous suggestions that cyclic AMP stimulated renin secretion, this could not be confirmed in the present preparation. Since there is no evidence that cyclic AMP or cyclic GMP (or their derivatives, dibutyryl cyclic AMP and 8 Br-cyclic GMP) enter the cells, it will be necessary to study their activity in isolated juxtaglomerular cells to define a possible role.

Retinal vein obstruction is a common complication of the retinopathy seen in patients with chronic hypertension. Previous studies have shown an abnormal control of intraocular pressure in response to changes of posture in patients with retinal vein obstruction. This paper describes the results of the investigation of the intraocular pressure response in 57 normotensive healthy adults and in 95 hypertensive patients, with a short study of 14 diabetic patients. Both hypertensive and diabetic groups showed abnormal responses. The possible significance of these findings as the expression of a fundamental anomaly by patients who develop either hypertension or diabetes is discussed.

The mechanisms of the cardiovascular and renin responses to vasoactive intestinal polypeptide (VIP) are unclear. Rabbit studies suggest that VIP-induced tachycardia is largely beta-adrenoceptor mediated, but that the renin response may be partially prostaglandin-dependent. To examine the relative importance of prostaglandins and reflex sympathetic activation in the haemodynamic and renin responses to VIP infusion in man, we completed two randomised single-blind crossover studies in two groups of six healthy male volunteers (aged 24-35 years). We recorded the effects of indomethacin and propranolol pretreatment on VIP-related changes in heart rate (HR), blood pressure (BP), forearm vascular resistance (FVR), plasma renin activity (PRA), plasma noradrenaline (PNA) and plasma arginine vasopressin (AVP) concentrations. Intravenous VIP (calculated dose: 6 pmol kg-1 min-1) produced cutaneous flushing, increased HR and PRA, decreased FVR, but did not alter mean arterial BP or AVP levels. Indomethacin (375 mg over 3 days) lowered basal PRA and propranolol (circa 40 mg i.v. over 60 min) decreased resting HR and increased FVR. Although indomethacin and propranolol reduced the absolute rise in PRA and HR, respectively, during VIP infusion, the percentage changes were no different from control. Neither drug altered the flush response to VIP and propranolol did not affect the fall in FVR. We conclude that the measured cardiovascular responses to VIP infusion in man are probably direct and do not involve a significant contribution from reflex sympathetic stimulation, nor prostaglandin release.