Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone greater than spironolactone greater than phenylbutazone (PBZ) greater than aspirin (ASA) greater than indomethacin (IDM). Concentration ratios required to obtain significant displacement of [3H]aldosterone were high but clearly within the therapeutic range for PBZ and ASA but not IDM. The analogues oxyphenbutazone (OBZ) and sodium salicylate (SS) were similar in binding activity to PBZ and ASA, respectively. Lineweaver-Burk analysis revealed that the inhibition of [3H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of [3H]aldosterone. In vivo injection of PBZ and ASA resulted in competition for [3H]aldosterone renal binding comparable to the in vitro studies. Administration of PBZ and OBZ to adrenalectomized rats resulted in significant salt retention whereas ASA and SS did not differ significantly from controls. Salt retention elicited by PBZ and OBZ was inhibited by spironolactone, a competitive mineralocorticoid antagonist. These data suggest that, despite nonsteroidal structures, PBZ and OBZ induce salt retention via a receptor-mediated mineralocorticoid pathway analogous to aldosterone action.

Plasma C-peptide and diagnosis of factitious hyperinsulinism. Study of an insulin-dependent diabetic patient with "spontaneous" hypoglycemia.

Factitious hyperinsulinism was suspected in a patient with an 11-year history of insulin-dependent, ketosis-prone diabetes mellitus who began to experience repetitive episodes of "spontaneous" hypoglycemia. Insulin mediation of the hypoglycemia was confirmed by documenting that urinary insulin and total extractable insulin in plasma increased during periods of hypoglycemia. Failure to detect significant amounts of human C-peptide by radioimmunoassay during periods of hypoglycemia or in response to stimulation with glucagon, leucine, or tolbutamide indicated that the insulin was not endogenous. The diagnosis of factitious hyperinsulinism was ultimately proved by the finding of radioactivity in the patient's urine after 131-I Hippuran was added to a vial of insulin found in the patient's room.