In patients with chronic uremia we have previously demonstrated a significant inhibition of the Na-K-ATPase enzyme which represents the specific receptor protein for cardiac glycosides. Since an endogenous inhibitor of this enzyme was previously shown to react with a digoxin antibody, in the present study we determined digoxin-like immunoreacting activity(ies) (DLIA) by a radioimmunoassay in 15 nondialyzed patients with chronic renal failure. In native serum, DLIA ranged from 0 to 1.70 ng/ml and was unrelated to the degree of renal failure. After gel filtration of serum, DLIA exclusively eluted in the small molecular weight salt (F III) and post-salt (FIV) fractions and averaged 0.22 ± 0.04 and 0.20 ± 0.05 ng/ml in fractions III and IV, respectively. Total activities ranged from 0.11 to 0.88 ng/ml with a mean of 0.42 ± 0.06 ng/ml and closely correlated with the degree of renal impairment (p < 0.001). The results confirm the presence of small molecular weight digoxin-like immunoreacting substance(s) in uremic serum. The variable activities in native serum and the lack of correlation between the degree of renal failure and DLIA in serum fraction IV previously shown to possess the Na-K-ATPase-inhibiting activity, however, indicate that DLIA may not reflect specifically the endogenous sodium pump inhibitor and that unspecific binding to this digoxin antibody of uremic toxins or other endogenous compounds, such as steroids other than aldosterone, may have occurred.

In six healthy subjects the role of renal prostaglandins (PG) in modulating the actions of the renin-angiotensin and renal adrenergic nervous systems on renal function was investigated. During high dietary sodium intake (350 mmol/day) for 4 days no changes in urinary excretion of PGE2, PGF2 alpha, noradrenaline or adrenaline were noted, whereas plasma renin activity (PRA) and urinary aldosterone excretion were suppressed. After 4 days of low sodium intake (35 mmol/day) urinary excretion of PGE2, aldosterone and noradrenaline, as well as PRA, had significantly increased. Inhibition of PG synthesis with indomethacin (2 mg/kg body weight) had no effects on renal function on day 5 of high sodium intake. Despite suppression of PRA and urinary aldosterone, indomethacin significantly reduced p-aminohippurate (PAH) clearance, glomerular filtration rate (GFR) and urinary sodium excretion on day 5 of low sodium intake, when urinary noradrenaline excretion remained high. The results point to the crucial role of the renal adrenergic nervous system in controlling renal vascular resistance and sodium conservation in healthy subjects during low sodium intake, which is unmasked when renal PG synthesis is blocked by indomethacin. Enhanced renal PG synthesis during sodium restriction therefore not only attenuates the vascular and tubular effects of the renin-angiotensin system but, more importantly, also those of the highly stimulated renal adrenergic nervous system.

1. The effects of frusemide, hydrochlorothiazide and spironolactone on the renal prostaglandin system, and the interference with their diuretic and natriuretic effects by inhibition of prostaglandin synthase, were investigated in healthy human subjects.2. Urinary excretion of prostaglandin E, was increased by the administration of frusemide (P < 0-05), hydrochlorothiazide and particularly by spironolactone, the least potent natriuretic agent (P < 0.05). A qualitatively similar but statistically insignificant rise in excretion of prostaglandin F,, was observed with hydrochlorothiazide.3. The rise in urinary excretion of sodium after frusemide and hydrochlorothiazide was significantly reduced by indomethacin, which also abolished the potassium-sparing effect of spironolactone and partially suppressed the diureticinduced rise in plasma renin activity.4. Indomethacin had no significant effect on urinary osmolality or free water absorption in the presence of frusemide or hydrochlorothiazide, but markedly enhanced urinary osmolality (P < 0.05) and free water absorption (P < 0.05) in the presence of spironolactone. 5. Increased renal prostaglandin activity after frusemide, hydrochlorothiazide and spironolactone may contribute to their natriuretic action which, in addition to the antikaliuretic effect of spironolactone, may be partially abolished by the presence of non-steroidal antiphlogistic agents.Correspondence: Professor H.