prorenoate-potassium and prorenone

The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double-blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4-35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs.

Topics: Adult; Canrenone; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Male; Metolazone; Mineralocorticoid Receptor Antagonists; Potassium; Spironolactone

Two new aldosterone antagonists, K-prorenoate [potassium 3(17 beta-hydroxy-6 beta, 7 beta-methylen-3-oxo-4-androsten-17 alpha-yl)propionate] and prorenone [3(17 beta-hydroxy-6 beta, 7 beta-methylen-3-oxo-4-androsten-17 alpha-yl) propionic acid gamma-lactone], its lactonic form, were studied in rat kidney using in vitro systems. Study of [3H]prorenone binding by a recently developed computer method indicated a high affinity, low capacity class of sites which are, seemingly, mineralocorticoid receptors. In competition experiments performed on [3H]aldosterone- and [3H]dexamethasone-binding sites, prorenone appeared to be a good competitor for mineralocorticoid-binding sites and a poor competitor for glucocorticoid-binding sites. The specificity of this molecule was further confirmed by its poor ability to displace [3H]dihydrotestosterone from rat prostate androgenic receptors compared to spironolactone [3-(3-oxo-7 alpha-acetylthio-17 beta-hydroxy-4-androsten-17 alpha-yl) propionic acid gamma-lactone]. In the same experiments, K-prorenoate demonstrated a very low affinity for the two types of receptors. The behavior of [3H]prorenone cytosolic complex was also studied in kidney mince experiments, which showed that the [3H]prorenone complex was not able to translocate into the nucleus. Prorenone inhibited the binding of [3H]aldosterone to the receptor and, consequently, the nuclear binding of aldosterone was not observed.

Topics: Aldosterone; Animals; Binding, Competitive; Cell Nucleus; Dexamethasone; Dihydrotestosterone; Kidney; Kinetics; Male; Mineralocorticoid Receptor Antagonists; Prostate; Rats; Receptors, Androgen; Receptors, Glucocorticoid; Spironolactone