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Multiple observations suggest local control of renal function via an intrarenal renin-angiotensin system, including evidence for local angiotensin (Ang) II production. Our first goal was to examine renal tissue Ang I:Ang II relations to ascertain whether Ang II formation differs in the circulation and in renal tissue. We have recently shown an authentic Ang II/Ang I ratio of 1.5:1 in renal lymph, the opposite of the Ang II:Ang I relation in plasma. Our second goal was to examine the influence of maximal angiotensin converting enzyme inhibition on these relations in plasma and in renal tissue. We used two converting enzyme inhibitors with differing lipid solubility, on the premise that tissue penetration and action might differ on that basis. We measured Ang I and Ang II in plasma and renal tissue of rats given an intravenous dose of either vehicle, enalapril, or ramipril, over a wide dose range, from 0.1 to 10.0 mg/kg i.v. Renal and plasma angiotensin concentrations were measured by high-performance liquid chromatography and radioimmunoassay. Whereas the Ang I concentration in normal rat plasma (273 +/- 84 fmol/mL) was over threefold the plasma Ang II concentration (83 +/- 12 fmol/mL), the ratio was reversed in the kidney (Ang II, 178 +/- 12 versus Ang I, 91 +/- 3 fmol/g; P < .001). Although ramipril and enalapril induced an indistinguishable dose-related acute fall in blood pressure and plasma Ang II concentration, lower enalapril doses were less effective in reducing renal tissue Ang I:Ang II conversion and Ang II concentration (P < .025).(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma insulin-like growth factor II (IGF-II) was not elevated although 71% of plasma IGF-II was present as big IGF-II (molecular weight 11 kDa) which probably represents a non-glycated form of pro-IGF-II. The GH response to hypoglycaemia was impaired and plasma levels of both IGF-I and the GH-dependent IGF binding protein (IGFBP-3) were low. A recently described unextracted assay directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II) allows direct plasma estimation (plasma E-21) of larger molecular forms of IGF-II without interference from normal IGF-II and IGF binding proteins. Basal values were grossly elevated (23.7 and 23.8 nmol/l). Treatment with GH led to an increase in the mean plasma glucose across 24 hours (4.25 +/- 0.21 mol/l (mean +/- SEM) before treatment, compared with 4.86 mmol/l +/- 0.17 following GH (P < 0.01)) and a reduction in hypoglycaemic attacks. The treatment was associated with a rise in IGFBP-3 and small increases in insulin like growth factors. Subsequent treatment with the somatostatin analogue octreotide did not produce a significant change in plasma glucose levels or insulin-like growth factors. Two courses of intrahepatic adriamycin restored elevated levels of E-21 to normal. Total IGF-II remained normal and IGF-I increased. GH treatment was successfully withdrawn with no effect on plasma glucose or growth factor levels. The patient remained free from hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: Increasing dietary sodium intake increases blood pressure in some subjects with essential hypertension. Atrial natriuretic factor (ANF) has a potential role in modifying these changes. The purpose of this study was to observe the blood pressure and plasma ANF responses to low and high sodium diets in subjects with essential hypertension to see if the plasma ANF and blood pressure responses were related., Design: An in-patient study of subjects taking their normal diet (day 1), a 12 mmol sodium diet for 6 days and a 250 mmol diet for 6 days., Patients: Seven men with essential hypertension., Measurements: Continuous 24 hour urine collections were analysed for sodium excretion. Blood pressure was recorded at 0900, 1205 and 1700 h on days 1, 7 and 13. Blood was taken at 0900 h (fasting supine overnight) and at 1200 h (after 2 hours erect posture) on the above days for plasma ANF, plasma renin activity (PRA) and serum aldosterone., Results: Urinary sodium excretion was (mean +/- SEM) 11 +/- 1 mmol on day 5 of the low sodium diet, and 294 +/- 17 mmol during the fifth day of the high sodium diet. Plasma ANF (supine and erect) was significantly lower (2.8 +/- 0.6, 1.6 +/- 0.2 pmol/l) on the low sodium diet when compared to the high sodium diet (8.6 +/- 2.4, 5.0 +/- 1.6 pmol/l (P < 0.05)). Supine and erect PRA and serum aldosterone were significantly higher on the low compared to the high sodium diet. Blood pressure responses were heterogeneous rather than bimodal. Mean arterial blood pressure was 107 +/- 3 mmHg on the low sodium diet and 111 +/- 4 mmHg on the high sodium diet (P < 0.05). Changes of blood pressure did not correlate with the changes of plasma ANF., Conclusions: Failure of plasma atrial natriuretic factor to rise with increasing dietary sodium did not therefore determine the blood pressure response to the change in dietary sodium. No link was established between plasma atrial natriuretic factor response and sodium sensitivity.

Subjects with Type 2 diabetes have been reported to have elevated total exchangeable sodium when compared with normal subjects. Sodium retention may contribute to the development of hypertension in these subjects. Atrial natriuretic factor may play a role in sodium and blood pressure homeostasis in Type 2 diabetes. We have studied plasma atrial natriuretic factor in 17 subjects with Type 2 diabetes (9M:8F; aged 49 +/- 2 years) (mean +/- SE) and in 17 age- (49 +/- 2 years) and sex-matched controls. Mean fasting blood sugar was 8.3 +/- 0.6 mmol l-1 in the diabetic subjects. After fasting from 2200h, subjects remained upright from 0745h until 0945h when blood was taken for plasma atrial natriuretic factor, plasma renin activity and serum aldosterone. Two litres of 0.15 mmol l-1 NaCl was infused intravenously between 1000h and 1400h while the subjects remained supine. Blood was taken hourly. At 0945h plasma atrial natriuretic factor was 3.8 +/- 0.4 pmol l-1 in diabetic subjects and 6.1 +/- 1.6 pmol l-1 in controls (NS), at 1000h after 15 mins supine 3.5 +/- 0.3 and 7.9 +/- 2.3 pmol l-1 respectively (p < 0.05) and increased to 9.4 +/- 1.5 and 9.4 +/- 1.2 pmol l-1 in diabetic subjects and controls at 1400h (NS; both p < 0.01 vs basal values). Serum aldosterone, plasma renin activity, blood pressure and urinary sodium output for 12h before, 4h during and 8h after the NaCl infusion were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Surprisingly inappropriately high levels of plasma atrial natriuretic factor (ANF) in subjects with Bartter's syndrome are lowered by indomethacin therapy. Indomethacin in normal man causes sodium retention. One might therefore expect plasma ANF to increase in subjects taking indomethacin as a secondary phenomenon. On the other hand a decrease of plasma ANF in normal man similar to that reported in Bartter's subjects may explain the sodium retention caused by the drug in normals. We have studied plasma ANF before and during a two litre, four hour normal saline infusion in eight healthy male subjects both before and following five days of oral indomethacin. Plasma ANF basally was 4.2 +/- 0.9 pmol/l (mean +/- SEM) on no drug and 5.2 +/- 0.6 pmol/l on indomethacin (NS). It increased in response to saline in both studies (7.8 +/- 1.5 pmol/l after two litres of saline on control day; 10.6 +/- 1.5 pmol/l on the drug at the equivalent time, both p less than 0.05 vs basal value). Overall response to saline as assessed by the area under the curve above the basal value of hourly measurements, was not different in the two studies. Basal serum aldosterone and plasma renin activity were reduced by indomethacin. Urinary sodium excretion was not different between groups during the 12 hours before, four hours during and eight hours after the infusion. We have shown that indomethacin does not alter basal or saline stimulated plasma ANF in normal man, a finding in contrast to that reported in subjects with Bartter's syndrome. The sodium retention caused by indomethacin in normal man is not therefore due to a decrease of plasma ANF.

Ten acromegalic subjects were studied in a trial designed to ascertain the optimum dosage of the somatostatin analogue SMS 201-995 (octreotide) in active acromegaly. Twenty-four-hour growth hormone (GH) profiles were assessed monthly for 6 months and again after 1 year of continuous therapy. After basal assessment octreotide was administered subcutaneously at a dose of 100 micrograms three times a day throughout the first month. The dose was increased by 300 micrograms/day at monthly intervals to a maximum of 1500 micrograms/day, unless serum GH fell to within set criteria. Eight patients completed the trial. One patient withdrew because of intractable diarrhoea while another died of causes related to his acromegaly and we have no evidence that octreotide played any part in his death. Mean 24-h GH fell from a basal level of 34.3 +/- SEM 7.6 mU/l to 8.0 +/- 1.3 mU/l (P less than 0.05) after 6 months. At 1 month (300 micrograms/day) mean GH was 13.6 +/- 2.2 mU/l and at 2 months (600 micrograms/day) 10.8 +/- 2.2 mU/l (P less than 0.05 vs 300 micrograms/day dose), and at 5 months (1500 micrograms/day) 11.3 +/- 2.0 mU/l (all P less than 0.05 vs basal). Analysis of group means revealed no significant difference between any dose schedules above 600 micrograms/day. After 1 year the mean GH of the group (n = 8) was 7.5 +/- 1.3 mU/l (P less than 0.05 vs basal). Three patients developed a deterioration and one an improvement in their glucose tolerance and three developed asymptomatic gallstones during the year of therapy. In conclusion, octreotide lowered GH levels in acromegaly over a 1-year period. We found no evidence that routinely increasing the dose beyond 600 micrograms/day was helpful.

The pathogenesis of hypertension associated with Cushing's syndrome is incompletely understood. We have studied basal and saline-stimulated levels of plasma atrial natriuretic hormone in 10 subjects with active Cushing's syndrome (8 F: 2 M), aged 43 +/- 4 years (mean +/- SEM). Ten age- and sex-matched normal control subjects were also studied. Subjects fasted from 22.00 h, rose at 07.45 h, and remained ambulant until 09.45 h when blood was taken for plasma ANH, plasma renin activity and serum aldosterone. Subjects then rested supine until 10.00 h when blood was again taken, and blood pressure recorded. Then, while subjects remained supine, 21 of 0.9% NaCl were infused between 10.00 and 14.00 h. Blood was taken hourly. Basal plasma ANH was 8.0 +/- 0.9 pmol/l in Cushing's subjects and 6.9 +/- 2.5 pmol/l in controls. Levels increased in response to saline in both groups, and became significantly higher in the group of patients with Cushing's syndrome (14.00 h level 21.3 +/- 3.9 vs 10.4 +/- 1.9 pmol/l; p less than 0.05). Serum aldosterone and plasma renin activity were not different between groups. Mean blood pressure was higher in patients (114 +/- 4 vs 91 +/- 7 mmHg; p less than 0.05). Urinary sodium excretion was not different between groups before saline, but during the four hours of saline was higher in Cushing's subjects (133 +/- 12 vs 67 +/- 11 mmols; N = 6; p less than 0.05). Our results suggest that during salt loading the exaggerated natriuresis seen in the Cushing's group may have been caused by ANH.

Human growth hormone releasing hormone (GHRH) fails to stimulate human growth hormone (GH) in hypercortisolism. In order to study whether the responsiveness to GHRH stimulation returns after cure of the hypercortisolism, the GH response to GHRH was examined in 8 patients at least 5 yr after they had undergone bilateral adrenalectomy as their sole treatment for Cushing's disease. None had current evidence of a pituitary macroadenoma. A group of 8 healthy subjects matched for age and sex formed the control group. All patients and subjects received an iv injection of GHRH 1 microgram/kg, after an overnight fast, blood samples were taken before and at 15, 30, 45, 60, 90 and 120 min. There was no statistical difference between the peak GH or area under curve (AUC) response (median, range) in the two groups studied (adrenalectomized peak GH 9.2 (4.6-32.0) vs 16.5 (7.5-63) mU/l, adrenalectomized AUC response 647.5 (344.2-1489.5) vs 1103.5 (339.7-5188.5) mU/l. Patients with Cushing's disease once cured of hypercortisolism, have a GH response to GHRH.

Atrial natriuretic factor (ANF) may play a role in the regulation of the changes of blood volume and vascular reactivity during pregnancy and when pregnancy is complicated by hypertension. Reports of plasma ANF levels during pregnancy are conflicting. We have prospectively studied plasma ANF levels during pregnancy in 25 women, and compared these with 20 age-matched non-pregnant women. Five women developed hypertension during pregnancy and a further five who remained normotensive had insulin-dependent diabetes mellitus. Plasma ANF was 6.8 +/- 1.2 (mean +/- SEM) and 6.3 +/- 0.9 pmol/l during weeks 8-15 and 24-31 of normal pregnancy (n = 15; vs non-pregnant levels (4.0 +/- 0.6 pmol/l) P less than 0.05, n = 20). Levels were 4.3 +/- 0.8 and 3.9 +/- 0.4 pmol/l during weeks 16-23 and 32-39. In the diabetic patients and in the group who developed hypertension levels were at no time different from the uncomplicated pregnancy group. Serum aldosterone increased as pregnancy progressed, but plasma renin activity remained unchanged. As plasma ANF was not different between those who did, and those who did not develop hypertension, early measurement of it will not predict who will and who will not develop hypertension during pregnancy.

The results of treating 10 acromegalic patients with octreotide are compared with those of bromocriptine. Bromocriptine (5 mg 4 times daily for 5 weeks) reduced mean growth hormone (GH) concentrations from 60 to 35 mU/l in 8 patients; a further 2 patients were unable to tolerate this dose. Ten patients (8 unresponsive to bromocriptine) received octreotide 100 micrograms 3 times daily, rising to 500 micrograms 3 times daily according to monthly 24-hour GH profiles. Two patients were withdrawn from octreotide therapy; in the remaining 8, mean GH fell from 36 to 11 mU/l after 6 months' therapy (a reduction to 22% of basal concentrations, compared to a reduction to 58% on bromocriptine). Asymptomatic changes of glucose tolerance and the development of gallstones were noted; further information on the latter is urgently required. In summary, the smallest effective dose of octreotide should be used and each patient should be monitored biochemically.

We have studied plasma ANF before and after a 4-h intravenous infusion of normal saline in eight subjects with active acromegaly and in eight age and sex-matched control subjects. Plasma ANF, serum aldosterone and blood pressure were measured basally and after 2 and 4 h and plasma renin activity basally and after 4 h. Basal plasma ANF was similar in each group (4.4 +/- 1.5 pmol/l (mean +/- SEM) in acromegalic subjects and 5.3 +/- 0.7 pmol/l in controls NS). Plasma ANF did not rise significantly after saline in the acromegalic group (2-h value, 5.9 +/- 0.9; 4-h value, 5.1 +/- 0.9 pmol/l) but did rise significantly in the control group (2-h value, 8.9 +/- 1.9; 4-h value 9.5 +/- 1.3 pmol/l, both values P less than 0.05 vs basal level). The 4-h ANF value was significantly higher in the control group than in the acromegalic group (P less than 0.05). Basal and stimulated serum aldosterone values were similar in the two groups. Plasma renin activity suppressed to a lesser extent in the acromegalic group after 4 h. The facts that basal plasma ANF was not raised in acromegalic subjects and did not respond to saline stimulation demonstrate that an abnormality of ANF control may be an important factor in the aetiology of the expanded sodium status of patients with acromegaly and hence may contribute to the hypertension seen in patients with growth hormone excess.

There is little information available concerning the presence or absence of a normal variation in the circulating concentration of atrial natriuretic hormone throughout a 24 h period. We have examined this in 8 normal subjects (aged 23-35 years) on a fixed 120 mmol Na+ diet. Circulating levels of ANH, plasma renin activity, serum aldosterone and serum cortisol were determined two-hourly during 24 h in a supine position. There was a significant change in the concentration of each of these four hormones during the study period (P less than 0.05). ANH: peak 8.5 (22.00 h), nadir 4.0 (12.00 h) (pmol/l); PRA: peak 1.7 (04.00 h), nadir 0.8 (22.00 h) (microgram.l-1.h-1); aldosterone: peak 350 (14.00 h), nadir 143 (22.00 h) (pmol/l); cortisol: peak 346 (08.00 h), nadir 51 (22.00 h) (nmol/l). Peak plasma ANH occurred at 22.00 h and with the exception of times 20.00 h and 10.00 h this value was significantly higher than all the other time means (P less than 0.05). The only other significant differences were between plasma ANH at 20.00 h and 06.00 h, 08.00 h, 12.00 h and 14.00 h, respectively (P less than 0.05). From midnight until 18.00 h, there was no significant difference between any of the time means. There was a peak in PRA at 04.00 h, while peak serum aldosterone and serum cortisol occurred at 14.00 h and 08.00 h, respectively. This study suggests that ANH may display a diurnal rhythm. Our findings provide further physiological evidence that plasma ANH and PRA may have a reciprocal relationship.

The relationships between plasma atrial natriuretic factor (ANF), blood pressure (BP) and age have not been clearly defined. We measured plasma ANF levels and BP in 128 normal subjects (65 male; 63 female; mean age 48 years, range 20-87 years) on no medication. In subjects of 75 years or less (n = 120) plasma ANF was 5.7 +/- 0.3 pmol/l (mean +/- SEM). Plasma ANF did not differ between sexes (males 5.6 +/- 0.4 pmol/l, females 5.9 +/- 0.4 pmol/l). There was a positive correlation between plasma ANF and age, correlation coefficient (r) = 0.46, systolic BP (r = 0.44), diastolic BP (r = 0.22) and mean BP (r = 0.37) (all P less than 0.01), but after multiple linear regression analysis plasma ANF only related significantly (P less than 0.01) to age and systolic BP once other factors had been excluded. We also measured plasma ANF after erect and supine posture and during a 21IV normal saline infusion given over 4 hrs (n = 24; age range 21-62 years) after an overnight fast. Mean plasma ANF was 5.9 +/- 1.1 pmol/l erect, 7.4 +/- 1.6 pmol/l supine and rose to 10.1 +/- 1.4 pmol/l after saline (both P less than 0.05 vs basal). Response to saline was assessed as the area under the curve of hourly measurements. Neither this nor peak ANF during saline infusion correlated with age. We conclude that basal plasma ANF is influenced by age and systolic BP but plasma ANF response to acute saline stimulation is not.

The oxidation by mitochondria of various rat tissues of proline, pyrroline-5-carboxylate (P5C) and a number of aldehydes has been studied and ADP/O ratios determined for liver mitochondria. High oxidative activity for proline and P5C was found only in the liver and kidney. During the oxidation by liver and kidney mitochondria of proline and P5C; glutamate, ammonia, aspartate and some ornithine accumulated, thus suggesting that proline may normally be converted to ornithine by mitochondria. The oxidation of P5C (glutamic acid semialdehyde) by a mitochondrial dehydrogenase may be the same enzyme that oxidizes succinic acid semi-aldehyde but different from that oxidizing acetaldehyde.