G A MacGregor

Evidence that patients with Addison's disease are undertreated with fludrocortisone.

Ten patients with Addisons disease, nine with undetectable plasma aldosterone, were found to be sodium and water depleted with high levels of plasma-renin activity despite receiving 0.05-0.1 mg/day of fludrocortisone and optimum doses of glucocorticoid replacement therapy. Fludrocortisone was withdrawn while patients were in hospital on a fixed sodium intake. There was an immediate natriuresis with a further increase in plasma-renin activity. When a daily dose of 0.3 mg of fludrocortisone was given all patients retained sodium and water and gained weight. There was a fall in plasma-renin activity in all patients and an associated fall in blood urea and plasma potassium, and an increase in plasma volume; oedema developed in some patients. At outpatient follow-up, the dose of fludrocortisone was adjusted according to plasma-renin activity. Most patients required 0.2 mg of fludrocortisone to maintain adequate sodium and water balance. These results suggest that patients with Addisons disease on 0.05-0.1 mg of fludrocortisone with undetectable plasma aldosterone levels are currently being undertreated with fludrocortisone. The best way of assessing sodium balance in these patients and their response to fludrocortisone is by measurement of plasma-renin activity in conjunction with 24 h urinary sodium excretion.

Interference by polar metabolites in a direct radioimmunoassay for plasma aldosterone.

The CIS Aldoctk-125 kit, a direct radioimmunoassay for plasma aldosterone, has been compared with a conventional technique involving solvent extraction. Results given by these two methods were poorly correlated (r = 0·445, n = 103), the direct assay giving higher values, particularly in patients being dialysed for renal failure. When the kit was modified to include an extraction step, results correlated well with those of the standard method (r = 0·952, n = 60). These observations suggested interference from polar metabolites. The possibility that glucuronides were responsible was investigated by measuring plasma aldosterone before and after hydrolysis with β-glucuronidase. Higher post-hydrolysis values confirmed the presence of glucuronides in plasma from normal subjects and patients with renal failure. Preliminary chromatographic studies on plasma from nine dialysis patients indicated the presence of tetrahydroaldosterone 3-glucuronide, and it is thought that this metabolite might contribute to the high values obtained with the direct assay.

Potassium channel stimulation in normal subjects and in patients with essential hypertension: an acute study with cromakalim (BRL 34915).

We studied the acute effects of the potassium channel opener cromakalim on blood pressure, the renin-angiotensin-aldosterone system and renal function in eight patients with essential hypertension and five normal subjects. In the hypertensive patients, blood pressure decreased significantly from 2 to 6 h after treatment with cromakalim 1.5 mg compared with placebo, but was unchanged in the normotensives. In both groups, the heart rate and plasma renin activity increased after the administration of cromakalim compared with placebo; however, plasma aldosterone was unchanged. There was no significant change in urinary electrolyte excretion in either group; urine flow decreased after the administration of cromakalim compared with placebo in normal subjects, but not in patients with essential hypertension. Cromakalim lowers blood pressure acutely in patients with essential hypertension but not in normotensive subjects. This may be due to a greater reflex response in the normal subjects or to specific effects of cromakalim on mechanisms causing the high blood pressure.

Angiotensin Converting Enzyme Inhibition Reveals an Important Role for the Renin System in the Control of Normal and High Blood Pressure in Man

Captopril, given for 5 days to normotensive healthy subjects caused a significant fall in blood pressure. The fall in mean supine blood pressure was greater on a low sodium diet (10 mmols/day) - 19.6% and was less on a high sodium diet (350 mmols/day) - 11% compared to the normal sodium intake (120 mmols/day) when the fall in blood pressure was 16.5%. Patients with essential hypertension who were studied on their normal diet had a similar fall in blood pressure for a given plasma renin activity. It seems likely that the predominant mechanism whereby captopril lowers blood pressure is through the inhibition of the formation of angiotensin II. If this is so, our results suggest that the renin system is an important control of both normal and high blood pressure when on a normal sodium intake.

Kinetics of Renal Sodium Excretion During Changes in Dietary Sodium Intake in Man - An Exponential Process?

The kinetics of urinary sodium excretion was studied during sodium restriction and sodium supplementation in normal subjects. Eight were studied on a normal sodium intake (24 h urinary sodium: 133.3 + 9.6 mmol) and then during 6 days on a low sodium intake of 10 mmol/day. Six other subjects were studied after equilibration on the low sodium intake for 7 days and then during 5 days on a high sodium intake of 350 mmol/day. 24 h urinary sodium excretion during sodium restriction was consistent with a first-order exponential process with an estimated half-life of 21.8 + 2.4 hours. During sodium supplementation there were corresponding increases in urinary sodium excretion reaching the new steady-state within 3 days but the behaviour of the urinary sodium excretion during the transition period was not consistent with a mono-exponential process. These observations support the concept that the control of sodium balance, during sodium restriction at least, is consistent with a first order proportional feed-back system. This kinetic approach should provide a useful framework for further studies on the dynamics of sodium excretion.

MODEST SALT REDUCTION LOWERS BLOOD PRESSURE AND URINARY ALBUMIN EXCRETION IN IMPAIRED GLUCOSE TOLERANCE AND TYPE 2 DIABETES: 5A.01

Reducing salt intake lowers blood pressure (BP), irrespective of initial BP levels. Tight control of BP in diabetics lowers the risk of strokes, heart attacks and heart failure and slows the progression of diabetic kidney disease. Despite the high cardiovascular risk and theoretical reasons for increased salt sensitivity in these patients, the current knowledge of the role of salt in regulating BP in diabetes is limited. We carried out a randomized double-blind crossover trial of salt restriction with placebo or slow sodium, each for 6 weeks in 26 diet controlled type 2 diabetics (T2DM) and 20 individuals with impaired glucose tolerance (IGT) with untreated normal or mild hypertension. Results: 24 h urinary sodium was 165 ± 9mmol/24 h on slow sodium and 117 ± 10mmol/24 h on placebo, with a reduction in urinary sodium of 49 ± 9mmol/24 h, equivalent to 2.9 g/day salt. This modest salt reduction significantly lowered systolic BP from 135.5 ± 2.0mmHg to 131.2 ± 1.9mmHg, a fall of −4.2 ± 1.5mmHg (p < 0.01). Diastolic BP was reduced from 81.3 ± 1.1mmHg to 79.7 ± 1.2mmHg, a reduction of −1.7 ± 0.9mmHg, with borderline significance (p = 0.055). Ambulatory BP was also lowered, with mean daytime BP reduced by −3.3 ± 0.9/−1.7 ± 0.9mmHg, night time BP by −4.3 ± 1.2/−2.3 ± 0.9 mmHg and mean 24 h BP by −3.3 ± 0.9/−1.8 ± 0.8mmHg. 24 h urinary albumin was reduced from 4.7 (IQR 3.2–12.1) mg/24 h on slow sodium to 4.2 (IQR 2.8–8.2) mg/24 h on placebo, although this reduction did not reach significance (p = 0.185). ACR was reduced significantly from 0.73 (IQR 0.5–1.5) mg/mmol on slow sodium to 0.64 (IQR 0.3–1.1) mg/mmol on placebo (p = 0.014). There was therefore a 12% reduction in ACR. Conclusions: A modest, easily achievable, reduction in salt intake in T2DM and IGT causes significantly and clinically relevant falls in BP. Furthermore, it reduces urinary albumin/creatinine ratio, which possibly has additional benefits on reducing both renal and cardiovascular disease beyond that obtained from a fall in BP alone. These findings strongly support the recommendation to reduce salt intake in diabetes as recommended in hypertension guidelines to less than 6 g/day.

ALTERING PLASMA SODIUM CONCENTRATION RAPIDLY CHANGES BLOOD PRESSURE DURING HAEMODIALYSIS: PP.23.420

Salt consumption leads to a small, transient rise in plasma sodium. There is increasing evidence that changes in plasma sodium may be an important factor in the blood pressure response to salt intake. Animal experiments have shown that a change in plasma sodium itself had a direct effect on BP, independent of extracellular volume. Ten participants were studied, in random order, on two separate haemodialysis sessions, one with dialysate sodium prescribed at 135mmol/L and the other at 145mmol/L. The experiments were carried out during the first 2 hours of the dialysis session with no ultrafiltration during the study period. BP and plasma sodium were measured at baseline before dialysis and every 30 min during the experimental period. Results: Dialysate sodium of 135mmol/L reduced plasma sodium from 139.5 ± 0.7mmol/L to 135.9 ± 0.5mmol/L (p < 0.001). Dialysate sodium 145mmol/L did not significantly change plasma sodium although plasma sodium was consistently higher with the higher dialysis sodium 145mmol/L. The maximum difference was 4.8 ± 0.3mmol/L at 120 min (p < 0.001). Predialysis sitting BP was 137/76 ± 7/3mmHg. Dialysis with a sodium concentration of 135mmol/L reduced SBP by 9 ± 3mmHg from 136 ± 6 mmHg at baseline to 127 ± 7mmHg at 120 min (p < 0.05). Dialysate sodium 145mmol/L did not significantly alter SBP. However, compared to dialysis sodium 135, SBP with dialysis sodium 145 was higher by 8 ± 3mmHg (p < 0.05) at 60 mins and 12 ± 5 mmHg (p = 0.05) at 120mins. DBP was not significantly changed during this study, but there was a significant positive relationship between plasma sodium and DBP. Conclusions: In this carefully conducted study, we have shown that alterations in dialysate sodium concentration had a rapid effect on plasma sodium and BP during isovolaemic dialysis in stable haemodialysis patients. Changes in dialysate sodium had significant and rapid effects on SBP, with lower dialysate sodium concentration associated with lower BP. This effect may be mediated by directional changes in plasma sodium. Future studies are required to explore the mechanisms by which changes in plasma sodium concentration influence BP.