The effect of long-term treatment with alpha-mercaptopropionylglycine was examined in 66 patients with cystinuria. Of the patients 49 took D-penicillamine before therapy, whereas 17 did not. Over-all side effects to alpha-mercaptopropionylglycine were common, and occurred in 75.5 per cent of the patients with and 64.7 per cent without a history of D-penicillamine treatment, compared to 83.7 per cent who suffered toxicity to D-penicillamine. Serious adverse reactions requiring cessation of therapy were less common with alpha-mercaptopropionylglycine. Among the patients who took both drugs 30.6 per cent had to stop taking alpha-mercaptopropionylglycine, whereas 69.4 per cent could not tolerate D-penicillamine. Of the latter group with toxicity to D-penicillamine before therapy, whereas 17 did therapy only 5.9 per cent had side effects to alpha-mercaptopropionylglycine of sufficient severity to require withdrawal. Alpha-mercaptopropionylglycine was equally as effective as D-penicillamine in reducing cystine excretion. During long-term treatment with alpha-mercaptopropionylglycine (average dose 1,193 mg. per day) urinary cystine levels were maintained at 350 to 560 mg. per day and urinary cystine was kept at undersaturated levels. Commensurate with these changes, alpha-mercaptopropionylglycine produced remission of stone formation in 63 to 71 per cent of the patients and reduced individual stone formation rate in 81 to 94 per cent. Thus, alpha-mercaptopropionylglycine has a definite therapeutic role in cystinuric patients with toxicity to D-penicillamine.

A B S T R A C T The effect of two prostaglandin synthesis inhibitors, indomethacin and meclofenamate, on angiotensin II (AII)-and III (AIII)-induced aldosterone release was studied in normal and sodiumdepleted conscious rats and in adrenal capsular cell suspensions obtained from normal rats. In normal rats, in vivo AII and AIII were equipotent in causing doserelated increases in serum aldosterone concentrations. Indomethacin decreased the basal serum aldosterone levels by 50% and serum renin levels by 43%. In addition, the steroidogenic effects of AII and AIII were reduced by 45 and 63% with 3 mg/kg of indomethacin and 63 and 73% with 10 mg/kg, respectively. In contrast, meclofenamate failed to alter basal serum levels of aldosterone or AII-stimulated aldosterone release but inhibited serum renin levels by 27% and the aldosterone-stimulating effect of AIII by 99%. Indomethacin (3 mg/kg) and meclofenamate (2 mg/kg) inhibited urinary prostaglandin (PG)E2 and PGF2G excretion by 63 1552 stimulated aldosterone release but inhibited that stimulated by AIII by 86%. The present findings suggest that prostaglandins modulate the effects of the renin-angiotensin system by stimulating the release of renin from the kidney and augmenting the steroidogenic effects of AII and AIII in the adrenal cortex.INTRODUCTION Recently, we have reported that both angiotensin II and III were equipotent in stimulating the release of aldosterone from the adrenal cortex; however, angiotensin III possessed only 30% of the pressor activity of angiotensin II (1, 2). These peptides were found to release prostaglandin (PG)E from the perfused kidney and mesenteric arterial vasculature (3-5). The released prostaglandins were vasodilators and antagonized the vasoconstriction caused by the angiotensins. Additionally, PGE stimulated the release of aldosterone from the adrenal, a property that was additive in effect with that of angiotensin II (6, 7). We, therefore, wondered if angiotensin II and III might simultaneously stimulate the release of aldosterone and PGE2 from the adrenal, and the released PGE2, acting as an intra-adrenal hormone, would also stimulate the release of aldosterone, thereby augmenting angiotensin-induced steroidogenesis. To test this hypothesis, the steroidogenic activity of angiotensin II and III were compared in conscious rats and adrenal cell suspensions in the presence and absence of the inhibitors of prostaglandin synthesis, indomethacin and meclofenamate (8).

Ketoconazole was used to probe the pathogenetic importance of the serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentration in 19 patients with well characterized absorptive hypercalciuria (AH). Patients were studied while receiving a constant metabolic diet before and after 2 weeks of ketoconazole administration (600 mg daily). Twelve of the patients were classified as ketoconazole responders, because in conjunction with a reduction of serum 1,25-(OH)2D from 113 +/- 36 to 70 +/- 26 pmol/L, intestinal 47Ca absorption decreased from 76.3 +/- 8.1% to 61.9 +/- 7.7%, and 24-h urinary Ca excretion declined from 7.6 +/- 1.4 to 5.7 +/- 1.1 mmol (P < 0.001 each). In these patients, intestinal 47Ca absorption was directly correlated with serum 1,25-(OH)2D levels and 24-h Ca excretion. In another group of 7 patients, termed ketoconazole nonresponders, despite reduction of 1,25-(OH)2D from 122 +/- 36 to 84 +/- 17 pmol/L (P = 0.015), there was no significant change in intestinal Ca absorption (76.0 +/- 8.2% to 72.1 +/- 10.6%) or 24-h urinary Ca excretion (7.3 +/- 1.3 to 7.2 +/- 1.0 mmol). In these patients, neither intestinal Ca absorption nor urinary Ca excretion was correlated with serum 1,25-(OH)2D levels. It, thus, appears that AH is a heterogeneous disorder comprised of both vitamin D-dependent and vitamin D-independent subsets. Although useful to probe the pathogenesis of AH, chronic treatment with ketoconazole is not recommended because of its generalized effects in inhibiting steroid synthesis.

SUMMARY Recently, we have found that tbe prostaglandin synthesis inhibitor, indometfaacin, reduced basal and angiotensin stimulated aldosterone release. To further test tbe possibility that prostaglandins (PGs) function as mediators of adrenal steroidogenesis, we examined the release of aldosterone, PGE,, and PGF ta under basal and stimulated conditions in isolated adrenal capsular cells in vitro. Angiotensin II and HI caused a dose-related increase in aldosterone release without significantly altering tbe release of PGE, or PGF*,. Indomethacin inhibited basal, angiotensin II, and angiotensin Ill-induced steroidogenesis by 40%, 15%, and 52% respectively. Additionally, it inhibited tbe release of PGE, by 60% in the control and angiotendn-treated cells. In indomethacin-treated cells, PGE, stimulated aldosterone release in sapraphysiologic doses; however, its steroidogenlc effect was not additive with angiotensin II. The prostaglandin precursor, arachidonic acid, increased the adrenal synthesis of PGE, and PGF ta in a dose-related manner without altering the synthesis of aldosterone. Similarly, the prostaglandin endoperoxide PGH, increased tbe synthesis of PGE, by 250-fold, yet failed to alter aldosterone synthesis. These findings indicate that PGE, does not mediate or modulate basal or angiotensin-stimulated steroidogenesis. Furthermore, it would appear that indomethacin may inhibit adrenal steroidogenesis via a mechanism other than inhibition of prostaglandin synthesis. Another prostaglandin synthesis inhibitor, meclofenamate, inhibited angiotensin III but not angiotensin II-induced steroidogenesis. Since both drugs simultaneously inhibited the urinary excretion of prostaglandin E a (PGE a ), and prostaglandin F( PGFin) reduced the adrenal prostaglandin content and reduced the adrenal conversion of "C-arachidonic acid to u C-PGEj and "C-PGF*,, it was suggested that adrenal prostaglandins mediate a portion of the steroidogenic effects of the angiotensins. This contention was also suggested by the observations of Saruta and Kaplan 2 that PGE! stimulated the release of aldosterone from adrenal cortical slices, an effect that was additive with angiotensin II. Subsequent studies confirmed the steroidogenic effects of PGE! and PGE, in vitro' 6 but not in vivo;* however, it should be mentioned that in each of the in vitro studies supraphysiological doses of the prostaglandins were required for the release of aldosterone.Our present studies were designed to further test the possibility that angiotensin stimulates the adrenal production of PGEj and that this PGEa augments the steroidogenic activity of the peptide. To accomplish this, we examined the effects of angiotensin II and III on the release of aldosterone, PGEj, and PGFjo in adrenal cell suspensions. Also, the effects of the precursors of these prostaglandins, arachidonic acid and prostaglandin cyclic endoperoxide (PGH 2 ), on the release of aldosterone were determined. MethodsMale Sprague-Dawley rats (225-300 g; Simonsen Laboratories) were used in these studies. ...

SUMMARY A deficiency in renal prostaglandins has been implicated in the pathogenesis of essential hypertension, particularly low renin hypertension. Previous studies of urinary prostaglandins as influenced by sodium balance and in essential hypertension have been handicapped by problems with assay methodology, inclusion of male subjects, and/or failure to standardize daily fluid consumption. We compared urinary excretion of prostaglandin E 2 (PGE,), prostaglandin F^ (PGF^), and thromboxane B 2 (TxB 2 ) in black and white normotensive and low-renin and normal-renin hypertensive women during two protocols producing sodium depletion (10 mEq sodium diet) and sodium loading (200 mEq sodium diet plus the fludrohydrocortisone Florinef, a synthetic mineralocorticoid). A constant fluid, potassium, and caloric intake was maintained throughout. Changes in plasma renin activity, urinary aldosterone excretion, and urinary kallikrein excretion were simultaneously assessed.As sodium intake decreased from 120 to 10 mEq sodium/day, increases in urinary PGF^ (502 ± 60 to 1222 ± 176 ng/24 hr, p < 0.01) and TxB ; (99 ± 33 to 216 ± 77 ng/24 hr, p < 0.05) excretion were observed in normotensive subjects. These increases were not observed in the hypertensive patients, possibly because less renin stimulation was achieved during the low sodium diet. Alternatively, subnormal prostaglandin production may have contributed to the lesser renin stimulation. Furthermore, urinary PGF, excretion in hypertensive patients during sodium depletion indicated strong influences of race and renin status; namely, black and normal-renin hypertensives increased urinary PGF^ excretion during sodium depletion whereas white and low-renin hypertensives did not. When white hypertensives and normotensive subjects consumed either 120 or 200 mEq sodium diet, there were no consistent differences in urinary excretion of PGE 2 , PGF^, or TxB 2 . With sodium loading, urinary PGE,, PGF^, and TxB 2 excretion did not change, whereas urinary kallikrein excretion increased. Urinary excretion of these prostanoids was therefore independent of mineralocorticoid and kallikrein effects upon the kidney. Thus, we found no evidence for a role of renal PGE 2 , PGF^, and TxB 2 in natriuresis in humans. Urinary excretion of these prostanoids was decreased in hypertensive patients only during sodium depletion. (Hypertension 4: 735-741, 1982) KEY WORDS • prostaglandins • thromboxane • kallikrein • renin • aldosterone natriuresis • mineralocorticoid escape • sodium loading