C. M. Kagawa

Sodium Retaining Activity of 19-Nor-Steroids in Adrenalectomized Rats

Summary 1. Sodium retaining activity of nine 19-nor-steroids was tested in adrenalectomized rats. 2. The 19-nor-analogs of de-soxycorticosterone, Reichsteins Compound S, hydrocortisone and corticosterone showed 5.1, 0.25, 0.25 and 0.06 times the potency of desoxycorticosterone, respectively. 3. Sodium retention equal to that of 6 μg desoxycorticosterone was not detected in 5 other 19-nor-steroids, which showed less structural resemblance to adrenocortical steroids. 4. Our results indicate that varying degrees of activity will be found with removal of the methyl group at carbon 10, depending upon specific structure of the steroid.

Blocking Urinary Electrolyte Effects of Desoxycorticosterone with Progesterone in Rats.

Summary Progesterone partially blocked the effects of desoxycorticosterone acetate (DCA) on the urinary ratio of Na/K in adrenalectomized rats by simultaneously reversing Na retention and K loss. Progesterone alone at large doses caused DCA-like reductions of the Na/K ratio. Tests of various dosage combinations with DCA suggest that blocking efficiency of progesterone is limited by its DCA-like property. The compound appears to be a competitive inhibitor of DCA and a unique example of a steroid with blocking and DCA-like effects in rats.

RELATIONSHIP OF PLASMA ALDADIENE LEVELS AND ANTIMINERALOCORTICOID EFFECTS OF SPIRONOLACTONE IN THE LABORATORY.

Summary Relationship of renal antimin-eralocorticoid effects with spironolactone and plasma levels of its δ6-metabolite, aldadiene, was investigated in adrenalectomized rats and in intact dogs treated with DCA. In comparative tests, spironolactone and aldadiene both given orally produced equal plasma levels of aldadiene, but unequal mineralocorti-coid-blocking effects. Potency ratios of approximately 3/1 and 5/1 were found for renal properties of spironolactone/aldadiene in rats and dogs, respectively. Interpretation of these data indicate that blocking activity of spironolactone is only partly accounted for by plasma titers of aldadiene.

Renal Electrolyte Effects of Synthetic 18-Hydroxylated Steroids in Adrenalectomized Rats

Summary Several synthetic 18-hydroxy-lated steroids lacking oxygen at carbon 11 were tested for mineralocorticoid properties in acute studies using adrenalectomized rats. A multiple dose assay with DCA described relative potencies of 4, 8 and 5% parenterally for 18-OH-DCA by the criteria of Na retention, K loss and reduction of the Na/K ratio in the urine. Approximately the same order of potency was found for the alcohol derivative, 18-OH-DOC. 18-OH-Progesterone was ineffective as a mineralocorticoid. No significant anti-mineralocorticoid activity was found with 18-OH-progesterone or 18-OH-DCA.

Action of Testosterone in Blocking Urinary Electrolyte Effects of Desoxycorticosterone.

Summary Large doses of testosterone blocked urinary electrolyte effects of desoxycorticosterone acetate (DCA) in adrenalectomized rats. The steroid reversed the Na/K response to DCA by simultaneously blocking Na retention and K loss. It did not affect Na/K in a manner opposing DCA action when given alone. These observations suggest competitive inhibition as the mechanism of effect for testosterone. Unlike progesterone, it was devoid of DCA-like effects on Na/K given alone, and it gave increasing DCA-blocking effect over a relatively wide range of doses.

Mineralocorticoid Effects of 9α-Fluorodeoxycorticosterone in Adrenalectomized Rats.∗

Summary The mineralocorticoid effects of 9α-fluorodeoxycorticosterone acetate were investigated in adrenalectomized rats. A quantitative 4-point assay gave potency estimates of 12 and 14.3 for the steroid relative to DCA, as judged by reduction of urinary Na excretion and the ratio of Na K. respectively. Thus, addition of a 9α-fluoro radical can increase mineralocorticoid activity in a steroid lacking oxygen function at carbon 11. These and other published data suggest that 9α-halogenation plays a singularly important part in high DCA-like activity of various 9α-halo corticosteroids.

Effects of Cortisone and Hydrocortisone on Sodium Excretion in Adrenalectomized Rats

Summary 1. The influence of time and dosage upon sodium excretion by rats was investigated after cortisone and hydrocortisone administration. 2. Results of time-response studies show that large doses cause initially weak and transient retention of sodium and subsequently strong excretion of the ion. Smaller doses reduce progressively duration of retention phase and hasten onset of secondary diuresis. 3. Two factors appear to influence the response of sodium excretion. During a fixed time-interval of urine collection, increasing doses cause excretion, no change and retention of sodium. Similar changes in excretion of the ion are seen with a given dose when collection interval is progressively shortened.

Ability of isopregnenolone-21-carboxylates to block renal effects of deoxycorticosterone and aldosterone in rats.

Summary Studies demonstrate that isopregnenolone-21-carboxylates are potent inhibitors of the renal electrolyte effects of deoxycorticosterone in adrenalectomized rats. Compound III, the most active in the series, was also effective against aldosterone. Available evidence indicates that the compounds affect electrolyte excretion by competition with aldosterone-like steroids at receptor sites in target tissue. The authors are indebted to Drs. R. R. Burtner, V. A., Drill and B. Riegel for generous advice and helpful criticism in preparation of the manuscript.