1. Diurnal changes in plasma concentrations of atrial natriuretic peptide (ANP), renin, angiotensin II, aldosterone, Cortisol and antidiuretic hormone were investigated in seven normal volunteers studied under standardized conditions of dietary sodium, posture and physical activity. After completion of the diurnal study serial measurements of these variables were continued during, and on recovery from, a 2 day period of severe sodium depletion. 2. Clear diurnal variations in plasma concentrations of renin, angiotensin II, aldosterone, Cortisol and antidiuretic hormone were observed. 3. Plasma ANP concentrations also varied significantly over 24 h. Values peaked about mid-day and a distinct trough in peptide concentrations occurred in the early evening. However, variations in plasma ANP values were of relatively small amplitude and not clearly independent of modest parallel shifts in sodium balance. 4. Changes in plasma ANP concentrations both within the diurnal study period and during sodium deprivation were closely and positively correlated with concomitant changes in cumulative sodium balance. 5. No simple parallel or reciprocal relationships between plasma concentrations of ANP, on the one hand, and concurrent plasma concentrations of other hormones or in the rate of urinary sodium excretion, on the other, were observed during the 25 h of the diurnal study.

1. To explore the effects of exercise on plasma atrial natriuretic peptide (ANP) concentrations, eight normotensive volunteers performed maximal treadmill exercise in sodium replete and deplete states. 2. Baseline immunoreactive plasma ANP concentrations were significantly lower during sodium depletion. During exercise plasma ANP rose in all subjects on both occasions. Plasma peptide responses were attenuated by sodium depletion with peak exercise levels only double baseline values, in contrast to the threefold increase in ANP concentrations observed when subjects were sodium replete. 3. Plasma renin and aldosterone concentrations also rose with exercise. In contrast to changes in plasma ANP, the responses of both were enhanced by sodium depletion.

1. The effects of polyethylene glycol (PEG) 200 administered by gavage on electrolyte and water excretion were investigated in the rat. 2. PEG 200 led, in intact rats, to dose-related increased drinking and to diuresis. 3. In the first 2 h after PEG 200 administration, water consumption in intact rats exceeded urine output. 4. PEG 200 enhanced the excretion of both sodium and potassium, but the sodium excretion was proportionately greater, resulting in an elevation of the urinary sodium/potassium ratio. 5. Bilateral nephrectomy was not accompanied by increased drinking in PEG 200-treated rats, although raised serum osmolality was seen. 6. Thus, given by gavage, PEG 200 is not an inert vehicle for drug administration.

1. Chlorothiazide (100 mg/kg body weight) was given by gavage daily to spontaneously hypertensive rats for 4 weeks. Another group of spontaneously hypertensive rats was given only tap water and served as control. 2. Measurements of total exchangeable sodium, blood pressure and weight were performed for 2 weeks before and for 4 weeks during treatment. 3. Before treatment, exchangeable sodium, blood pressure and weight were similar in the two groups of rats. 4. Chlorothiazide significantly attenuated the blood pressure increase in spontaneously hypertensive rats, the effect being most marked during the first 2 1/2 weeks of treatment and less thereafter. 5. Rats in the chlorothiazide-treated group gained weight more slowly than did those of the control group. 6. Exchangeable sodium, expressed as mmol/kg body weight, did not differ significantly between the two groups at any stage. 7. When exchangeable sodium was expressed as mmol/rat, there was a more gradual rise in the chlorothiazide-treated animals, in accordance with their slower gain in weight. 8. There was no temporal association between the antihypertensive effect of chlorothiazide and changes in exchangeable sodium. 9. Thus whereas chlorothiazide treatment of spontaneously hypertensive rats slows the increase of both weight and exchangeable sodium, other mechanisms are apparently responsible for the antihypertensive action of the drug.

1. Exchangeable sodium (Na E ), plasma active renin concentration and blood pressure were measured in rats with a sole remaining kidney before and after the development of hypertension induced by clipping of the single renal artery and again after unclipping. 2. Control observations were made in sham-clipped and sham-unclipped uninephrectomized rats. 3. Renal artery clipping caused hypertension and expansion of Na E , the latter being sustained throughout the 6 weeks during which the renal artery was constricted. 4. Hypertension in the clipped rats was progressive over 6 weeks, whereas the expansion of Na E was not; thus the two measurements were not significantly correlated. 5. Two rats which remained normotensive after clipping did not show expansion of Na E . 6. Plasma active renin was elevated in comparison with the sham-clipped controls on the day after clipping, but not thereafter. 7. Unclipping in hypertensive rats was followed by a return of Na E and blood pressure to control values. 8. Both the sustained expansion of Na E and the transient rise in active renin probably contribute to the development of hypertension in this model, but neither alone nor together do they provide a full satisfactory explanation.

1. Arterial pressure, exchangeable sodium (Na E ), exchangeable potassium (K E ) and plasma concentrations of sodium, potassium, urea, angiotension II and aldosterone were measured in 34 patients with untreated Conn's syndrome before surgical removal of their adenoma. The study was repeated in 23 patients between 3 and 12 months after the operation. 2. Plasma aldosterone, Na E and plasma sodium concentration were higher and K E and plasma potassium concentration were lower than predicted normal. Surgery corrected these abnormalities, also reducing blood pressure from an average of 183/112 to 138/86 mmHg. 3. Systolic blood pressure was positively correlated with plasma and exchangeable sodium and negatively correlated with plasma potassium concentration. The relation of Na E and arterial pressure was closer in old than in young patients. None of these correlations was significant after operation. Before operation plasma urea was insignificantly related to arterial pressure but after operation a significant and positive correlation emerged. 4. A relation between arterial pressure and Na E is to be expected in a state of mineralocorticoid excess but the different correlation in old and young patients was not expected. A similar difference exists in patients with essential hypertension.

1. Exchangeable sodium (Na E ), plasma electrolytes and arterial pressure were measured in 121 normal subjects and 91 patients with untreated essential hypertension (diastolic >100 mmHg), 21 of whom had low-renin hypertension. Plasma concentrations of renin, angiotensin II and aldosterone were measured in all hypertensive patients, total body sodium, total body potassium and exchangeable potassium (K E ) in some patients. 2. Mean Na E was not different in normal and hypertensive subjects provided the two groups were matched for leanness index. In the subgroup of young hypertensive patients aged 35 years or less mean Na E was below normal. Na E was not related to arterial pressure in normal subjects but in hypertensive patients there were positive and significant correlations of arterial pressure with Na E and with total body sodium. 3. Na E and total body sodium increased with age in hypertensive but not in normal subjects. Partial regression analysis suggested that the correlation of Na E with arterial pressure was not explained by an influence of age. 4. Mean Na E was not increased and mean K E was not decreased in patients with low-renin hypertension. 5. Plasma potassium concentration, K E and total body potassium correlated inversely and significantly with blood pressure in hypertensive patients. These correlations were more marked in young than in old patients. 6. Multiple regression analysis showed that the combination of Na E and plasma potassium concentration ‘explained’ more of the variation of systolic blood pressure in hypertensive patients than it did in normal subjects. Plasma potassium concentration ‘explained’ more of the variation in young hypertensives and Na E ‘explained’ more in older patients. 7. Our findings suggest that changes of plasma and body potassium are important in the earlier stages of essential hypertension and that changes of body sodium become important later.

1. Exchangeable sodium (Na E ) was measured serially in rats given a sodium-free diet to eat with sodium chloride solution (85 mmol/l) containing 22 Na to drink. 2. After 15 days, nine rats had a left renal artery clip applied; nine had a sham operation. 3. There was no significant difference in Na E between the two groups during the 6 week period after clipping, at the end of which blood pressure was 189 ± 8 mmHg (mean ± sem ) in the clipped group and 150 ± 2 mmHg in the sham-operated group ( P < 0·001). 4. When the clips were removed blood pressure in the hypertensive group fell to 144 ± 4 mmHg. 5. On the first day after removal of the clip Na E was significantly lower in the clipped group than in the sham-operated group, but there were no significant differences thereafter. 6. Total body sodium (TBNa), measured at death, was consistently higher than Na E by a mean of 1·25 ± 0·08 mmol, in hypertensive and control rats alike. 7. We conclude that changes in sodium balance are not a necessary accompaniment of the development of hypertension in this two-kidney one-clip rat model.

1. Potassium was infused intravenously in an incremental fashion and the plasma aldosterone responses were measured in conscious beagle dogs at five different intakes of dietary sodium. 2. Potassium/aldosterone dose—response curves were constructed for each dietary sodium regimen. 3. The rate of increase of plasma potassium during graded potassium infusion became progressively greater with increasing sodium depletion. 4. Regression lines of plasma aldosterone on plasma potassium were progressively elevated and steepened with increasing sodium depletion. 5. The alteration of these dose-response curves could in part have been the result of chronic elevation of plasma potassium and angiotensin II, and depression of plasma sodium, with sodium deprivation. 6. By contrast, acute changes in plasma angiotensin II or sodium concentrations across incremental infusions of potassium did not explain the progressive changes in the potassium/aldosterone dose—response curves. 7. The steepest part of the plasma aldosterone response curve was in the plasma potassium range 4–6 mmol/l. 8. Maximum achieved aldosterone levels were similar to or greater than those attained during angiotensin II infusion in previous studies in beagle dogs. 9. Potassium, like angiotensin II and adrenocorticotropic hormone, becomes a more effective stimulus to aldosterone with sodium depletion, thereby facilitating the preservation of sodium homoeostasis.

1. We studied the effect of oral prazosin on blood pressure, plasma active renin and angiotensin II in 16 recumbent hypertensive patients between 09.00 and 12.00 hours. 2. In untreated patients there were no significant changes in blood pressure, plasma active renin or angiotensin II during the 3 h period. 3. After an initial dose of prazosin (2 mg) there was a significant fall in recumbent blood pressure with progressive increases in plasma active renin and angiotensin II concentrations. 4. After 3–4 weeks' treatment with oral prazosin only, recumbent blood pressure at 09.00 hours, 15 h after the last dose of prazosin, was significantly lower than before treatment, but plasma active renin and angiotensin II were not significantly different from untreated values. 5. After the usual morning dose of prazosin, blood pressure did not change, but there were significant rises in plasma active renin and angiotensin II, less marked than after the first dose of prazosin. 6. Prazosin therefore stimulates the renin—angiotensin system acutely, both after the initial dose and during long-term therapy; however, no effect on renin and angiotensin II is apparent 15 h after the last dose of prazosin.

1. Arterial pressure, plasma electrolytes and exchangeable sodium were measured in 91 patients with essential hypertension and in 121 normal control subjects. Total body sodium, exchangeable potassium and total body potassium were also measured in some of the hypertensive patients. 2. Mean plasma sodium concentration was slightly but significantly lower in the hypertensive patients as a group, but mean values for other electrolyte measurements were close to normal or predicted normal. 3. Exchangeable sodium was not related to arterial pressure in normal subjects but in hypertensive patients exchangeable sodium correlated significantly with systolic and diastolic pressures. These correlations were significant with two methods of expressing exchangeable sodium, in the whole group of patients, in men and in older patients. Exchangeable sodium was not significantly related to arterial pressure in young patients. 4. Total body sodium also correlated significantly with systolic and diastolic pressures in hypertensive patients. 5. Exchangeable sodium was significantly related to age in hypertensive patients but not in normal subjects. Mean exchangeable sodium was significantly lower than normal in young patients. 6. Plasma potassium concentration was not related to arterial pressure in normal subjects but in essential hypertensive patients plasma potassium concentration, exchangeable potassium and total body potassium correlated negatively with systolic and diastolic pressures. These correlations were also significant in young, but not in old patients.

1. Plasma levels of vasopressin were found to be significantly higher in 29 patients with malignant hypertension than in 106 normotensive control subjects (13 ± 2 ng/l vs 5.8 ± 0.2 ng/l, P < 0.001). 2. No correlation was apparent between blood pressure and circulating vasopressin. 3. An acute, incremental infusion of vasopressin (0.125, 0.25 and 0.5 ng min −1 kg −1 ) in nine patients with mild-moderate essential hypertension produced only minor changes in blood pressure despite achieving plasma levels spanning those seen in malignant hypertension. 4. Despite a small increase in pressor sensitivity to vasopressin in hypertensive subjects it is thus unlikely that an acute vasoconstrictor effect of this peptide is important in the pathogenesis of malignant hypertension.

1. The converting-enzyme inhibitor captopril has been given in doses up to 450 mg daily to hypertensive patients with renal artery stenosis and to patients resistant to other therapy. 2. Captopril alone was effective in controlling hypertension in renal artery stenosis, irrespective of whether pretreatment plasma angiotensin II was raised or normal, except in one man with overall renal impairment. 3. In one woman with the hyponatraemic hypertensive syndrome secondary to renal artery thrombosis, captopril restored depleted exchangeable sodium and potassium to normal. In the other cases of renal artery stenosis with normal renal function, exchangeable sodium and total body potassium were not significantly altered, and there were no marked changes in plasma sodium and potassium. 4. The combination of captopril with a diuretic controlled blood pressure long-term in every case of previously resistant hypertension. 5. Within 2 h, captopril induced highly significant falls in arterial pressure, in plasma angiotensin II and aldosterone, with converse increases in plasma active and total renin and blood angiotensin I. 6. The initial fall in plasma angiotensin II was closely related to the concomitant fall in diastolic pressure. 7. The pattern of change in circulating renin, angiotensins I and II and aldosterone was maintained during long-term therapy, whether or not a diuretic was added. There was no tendency for plasma angiotensin II to increase despite sustained elevation of active renin and angiotensin I.

1. Arterial pressure and exchangeable sodium (Na E ) were measured in patients with Conn's syndrome, essential hypertension, renal artery stenosis and chronic renal failure. Comparison was made with a control group. Urine sodium excretion was measured separately from the two kidneys in patients with renal artery stenosis. 2. Compared with control, mean Na E was significantly increased in Conn's syndrome, and was normal in essential hypertension, renal artery stenosis and chronic renal failure. 3. The correlation of arterial pressure with Na E was positive and significant in Conn's syndrome, essential hypertension and chronic renal failure. 4. In contrast the correlation was significantly negative in unilateral renal artery stenosis. Patients with lowest Na E had hyponatraemia, hypokalaemia and secondary hyperaldosteronism. 5. Urinary sodium excretion from the unaffected kidney in unilateral renal artery stenosis correlated positively with arterial pressure, possibly reflecting the phenomenon of pressure-natriuresis. Patients subsequently responding least well to surgery excreted least sodium from the untouched kidney for a given arterial pressure. 6. The findings suggest important roles for arterial pressure in the regulation of sodium balance (predominant in renal artery stenosis), and for sodium balance in the regulation of arterial pressure (predominant in Conn's syndrome). The observations in essential hypertension are compatible either with an exact balance between these mechanisms or with the existence of some other mechanism raising blood pressure.

1. A patient presented with mild hypertension, a raised plasma total renin concentration but a normal plasma angiotensin II concentration. The discrepancy was due to a high concentration of inactive renin in the plasma. 2. A renal carcinoma was detected and removed. The tumour contained a higher proportion of inactive renin than was found in uninvolved areas of the kidney. After unilateral nephrectomy, the plasma concentration of inactive renin fell to normal. 3. Six months later, plasma inactive renin concentration again increased and a metastasis was detected in a rib. Excision of the rib together with radiotherapy resulted in a fall in plasma inactive renin to normal. 4. The inactive renin in plasma and tumour extracts was activated to the same extent by acid treatment and by trypsin.

1. Infusion of angiotensin II into dogs at constant dose over 2 weeks caused a progressive rise in arterial pressure. 2. When the infusion was stopped the pressure dropped slowly from hypertensive levels over 48 h. 3. Dose—response studies at weekly intervals showed progressive elevation, without steepening, of the plasma angiotensin II—blood pressure curve. 4. Thus, during prolonged administration of angiotensin II, a given plasma concentration of the peptide can sustain a higher arterial pressure than it can during acute infusions.

1. Total-body neutron-activation analysis in vivo was carried out in 11 hypertensive subjects to measure simultaneously the total body content of sodium, chlorine, calcium, phosphorus and nitrogen. 2. There was a highly significant correlation between total body sodium measured by activation analysis and total exchangeable sodium measured by a standard isotope-dilution technique ( r = 0·92, P < 0·001). Exchangeable sodium averaged 80·3% of total body sodium. 3. The measured values of chlorine, calcium, phosphorus and nitrogen were similar to those for healthy subjects reported by others. 4. Activation analysis in vivo appears promising as an additional tool for investigating sodium metabolism in hypertension, as it is the only method available for determining the total body content of this element. The radiation dose (1 rem) is sufficiently low to permit repeated measurements in the same subject.

1. Labetalol, a compound with both α- and β-adrenoreceptor-blocking actions, was given intravenously (1·5–2·0 mg/kg) in twenty recumbent hypertensive patients. 2. There was a rapid reduction in systolic and diastolic pressures in all, maintained up to 24 h in some subjects. 3. Severe hypotension was not seen in recumbent subjects, but postural hypotension was common. 4. Labetalol caused significant lowering of heart rate. 5. Labetalol induced significant and related lowering of plasma angiotensin II and aldosterone concentrations, most obviously when these were initially high. 6. In a cross-over comparison in five patients against 10 mg of propranolol intravenously, labetalol was more effective in lowering blood pressure, but less effective in lowering pulse rate or plasma angiotensin II.

1. Intravenous frusemide produced in normal subjects a prompt rise of plasma renin concentration which correlated with urinary sodium. 2. The renin response to frusemide was suppressed in patients with primary hyperaldosteronism. 3. In patients with low-renin hypertension and normal renin essential hypertension, the renin response to frusemide was similarly suppressed. 4. Suppression of the renin response to frusemide is therefore a feature of hypertension not confined to patients with primary hyperaldosteronism and low-renin hypertension. 5. Thus low-renin hypertension does not appear to constitute a distinct diagnostic entity. 6. It is suggested that suppression of the renin response is part of a long-term renal adaptation to high blood pressure.

1. Prolonged treatment with spironolactone in low-renin hyperaldosteronism invariably corrects plasma electrolyte abnormalities and usually lowers blood pressure. 2. Total exchangeable sodium, total body water, extracellular fluid and plasma volumes are reduced; total exchangeable and total body potassium, plasma renin and angiotensin II concentrations are increased. 3. Spironolactone is similarly effective in patients with apparently isolated deoxycorticosterone (DOC) excess; also in suspected mineralocorticoid excess not associated with elevation of aldosterone or DOC. 4. Studies of amiloride reveal similar effectiveness to spironolactone in low-renin hyperaldosteronism and in suspected mineralocorticoid excess.

1. Compared with sixteen control animals infused with saline, plasma renin-substrate concentration increased twofold ( P < 0.001) in twenty-two rats following infusion of angiotensin II at a mean rate of 191 ng kg −1 min −1 for 13 h. 2. The change was not attributable to an overall increase of plasma protein concentration.

1. The changes of peripheral venous plasma renin concentration (PRC) induced by head-up tilting were studied in four patients with orthostatic hypotension. 2. Two of the patients had the Holmes—Adie syndrome and tests of autonomic function suggested that they had an afferent block from baroreceptors with intact efferent pathways; the others had no evidence of the Holmes—Adie syndrome and investigations suggested that they had interruption of efferent sympathetic pathways. 3. In the two patients in whom lesions of the afferent side of baroreceptor reflexes were suspected, a marked increase in PRC occurred with upright tilting, whereas no change in PRC occurred in the two patients thought to have an efferent sympathetic block. 4. During repeated tilting, supine blood pressure and PRC increased progressively in the two patients with suspected afferent block, but not in the two patients with suspected efferent block. 5. It is suggested that an increase in plasma renin may contribute to the supine hypertension sometimes observed in patients with orthostatic hypotension. 6. It is also suggested that renin release does not require intact autonomic reflexes although certain components of efferent sympathetic pathways, not dependent on baroreceptor reflexes, may be important.

1. The relationship of changes in plasma renin and plasma aldosterone concentration to electrolyte balance was studied during total fasting and during sodium deprivation followed by total fasting. 2. During simple sodium deprivation obese subjects lost significantly more sodium than lean subjects, but the rise in plasma renin concentration (PRC) was similar in the two groups. 3. During total fasting there was a failure of PRC to increase in the expected manner despite a marked negative sodium balance. In the early stages of the fast, PRC decreased in nine of eleven subjects while subsequently it increased in all subjects. 4. During sodium deprivation PRC and plasma aldosterone concentration (PAC) rose in all subjects studied, but in the first few days of a period of total fasting immediately following, there was a fall in PRC in eight of ten subjects studied, while PAC continued to rise in five of six subjects in whom it was measured. 5. These results are discussed in relation to the concept of the renin-angiotensin system as a regulator of aldosterone secretion.

1. Quantities of renin associated with single deep and superficial glomeruli were compared in sodium-loaded and sodium-deprived rabbits. 2. Significantly greater quantities of renin were found in association with both superficial and deep glomeruli in the sodium-deprived animals.

1. In anaesthetized dogs the rate at which renin was released into the circulation of the right and left kidneys was estimated from renal blood flow, haematocrit, and the V-A renin concentration difference across the kidney. Renin was also measured in samples of renal lymph collected at the same time. 2. The effect on renin release of reducing blood flow in one kidney was studied. For all observations (control and experimental), renal venous plasma renin concentration (RVR) was directly related to arterial plasma renin concentration and to renin release; RVR was inversely related to renal plasma flow. 3. The concentration of renin in renal lymph was considerably higher than that in renal venous plasma taken at the same time. Arterial plasma renin concentration was directly related to the sum of the rates at which renin was released from the two kidneys. 4. Clamping the renal artery of one kidney for 1 hr led to a marked reduction of renal blood flow, to a marked increase in RVR and to a variable change in renin release. Removal of the clamp was followed by increased renin release and by reversal of a previously positive V-A renin difference in the control kidney. 5. On several other occasions negative V-A renin differences were observed. That is, more renin appeared to enter the kidney in arterial blood than left in the renal vein.