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

Abstract

A B S T R A C T 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 > spironolactone > phenylbutazone (PBZ) > aspirin (ASA) > indomethacin (IDM). Concentration ratios required to obtain significant displacement of ['H]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 [8H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of ['H]aldosterone.In vivo injection of PBZ and ASA resulted in competition for [8H]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.

Prostaglandins Participate in the Regulation of NaCl Absorption in the Diluting Segments of the Nephron in vivo: Effects of Furosemide

“…Indomethacin significantly de creased mean U p^V both during control (0.51 + 0.09 pmol/min; p<0.025)and furo semide administration (0.56 + 0.13 pmol/ min; p<0.025). Previous studies have suggested that indomethacin may have intrinsic sodium-re taining activity by competing with aldoste rone for renal 'mineralocorticoid receptors' [26]. The present results, both with potas sium retention and with marked chloride retention following indomethacin treat ment, would seem to exclude such an intrin sic activity of indomethacin as the mecha nism of the observed salt retention.…”

Mifepristone Promotes Adiponectin Production and Improves Insulin Sensitivity in a Mouse Model of Diet-Induced-Obesity

“…Indeed, identification of the molecular mechanisms underlying the effects of mifepristone on metabolic functions remains to be resolved. We tested several other pharmacological agents chemically or pharmacologically related to mifepristone: GR antagonists, pregnenolone and DHEA; synthetic progestin causing abortion, levonorgestrel; MR antagonist, spironolactone [8,31–34]. None of these drugs swere capable of promoting adiponectin secretion ( Hashimoto et al unpublished observation ).…”

Biochemical and haematological effects of phenylbutazone in horses

“…Their data, however, did not entirely support this view (Lees and Michell 1979) and they subsequently confirmed that plasma volume was reduced, even to a degree associated with shock, as a result of intestinal protein loss (Snow et a1 1980). Salt and water retention is a widely acknowledged effect of phenylbutazone, which has inherent aldosterone-like properties and also, through interference with renal prostaglandin synthesis, potentiates the effect of antidiuretic hormone (Feldman and Couropmitree 1976;Dunn and Hood 1977;Hall, Hensey, O'Neill and Sheehan 1978). It has also been shown to interfere with the renin/angiotensin system in horses (Purohit et a1 1979).…”

“…Among the reported causes of hypomagnesaemia (Parfitt and Kleerekoper 1980) malabsorption seems a possibility in view of the likelihood of enteric protein loss. Although hypomagnesaemia is not a documented side effect of phenylbutazone, it is a recognised consequence of hyperaldosteronism and the drug does bind to the receptor sites for this hormone (Feldman and Couropmitree 1976).…”