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Saralasin, an angiotensin II antagonist, was infused into 49 patients with renal artery stenosis, 10 patients with essential hypertension and normal renal arteriograms, and five patients with "low-renin essential hypertension." Renal venous renin and differential renal function studies were used to assess the functional significance of arterial stenoses. "Response" to saralasin, evidenced by a fall in blood pressure during infusion, occurred in no patients with "low renin" hypertension and in only 20% of patients with normal renal arteriograms. In contrast, saralasin "response" occurred in more than 80% of patients with renal artery stenosis and lateralizing functional studies and 100% of cases of "proven" renovascular hypertension (cure or improvement of hypertension after operative treatment). We suggest that saralasin infusion might be a valuable screening test for the recognition of renovascular hypertension. [ABSTRACT FROM AUTHOR]

Plasma levels of the delta5-pregnenes, pregenolone and 17-OH-pregnenolone, were measured in patients with disordered steroidogenesis. While 17-OH-pregnenolone was within the normal range in patients with hypercortisolemia due to Cushing's disease, ectopic ACTH or adrenal adenrenal adenoma, 4 of 6 patients with an adrenal carcinoma had elevated levels of this precursor. Thus, elevated plasma 17-OH-pregnenolone levels in patients with Cushing's syndrome indicate adrenal carcinoma, although a normal value does not exclude this diagnosis. Abnormal resistance of delta5-pregnenes to suppression with dexamethasone proved useful in detecting the presence of residual tumor in the post-operative evaluation of adrenal carcinoma. Basal plasma pregnenolone was within the normal range in 19 of 20 patients with Cushing's disease and was invariably normal in patients with other varieties of hypercortisolism. Since acute administration of ACTH causes marked elevation of delta5-pregnene levels while patients with chronic ACTH excess (Cushing's disease and ectopic ACTH production) have normal levels, it is suggested that ACTH has a chronic influence on the intraadrenal utilization of delta5-pregnenes in addition to stimulating their formation. In pre-menopausal women with idiopathic hirsutism, basal levels of both delta5-pregnenes were elevated (P less than 0.001). Following dexamethasone administration the absolute decrease in delta5-pregnenes levels was greater than that seen in normal subjects. This observation indicates that the metabolism of delta5-pregnenes is abnormal in patients with idiopathic hirsutism.

This is a retrospective analytic review of 208 patients with hyperparathyroidism studied and treated at Vanderbilt University Hospital from 1935 to 1980. Follow-up in these patients has been completed to date or to death in a great majority of patients. Results indicate the value of excision of isolated adenomas and of subtotal parathyroidectomy for primary and secondary hyperplasia.

LH is composed of isoforms which exhibit microheterogeneity. We recently demonstrated that a particular ovine or porcine LH preparation (G100-fr.3) stimulates kidney growth. This study was conducted to clarify the physiological role of this renotropic activity and other extragonadal effects of the ovine LH preparation in CD-1 mice. Hypophysectomy caused a significantly greater reduction in relative dry kidney weight (i.e. g/100 g body weight) when compared to adrenalectomy, castration, thyroidectomy, and castration plus thyroidectomy. Supplementation with G100-fr.3 in these animals partially restored not only kidney size but also DNA, RNA and protein content. Treatment with standard LH preparations (NIDDKoLH24 and G3-268DA), as well as PRL, GH, FSH and TSH, failed to reverse the renal atrophy induced by hypophysectomy and castration. Administration of testosterone to castrated hypophysectomized mice increased kidney weight and RNA content, but not renal DNA. The relative dry kidney weight increased significantly at the onset of puberty in intact male mice, but not in castrated males or intact female mice. In addition, human CG increased kidney size in hypophysectomized male mice, but not in castrated hypophysectomized animals. These findings indicate that LH isoforms may regulate kidney growth in the male mouse both directly as a renotropin stimulating hyperplasia and indirectly as a gonadotropin via testicular androgen, producing cellular hypertrophy. It was also noted that G100-fr.3 decreased hepatic weight, DNA, RNA and protein, but produced no significant change in the spleen, heart or adrenal glands in castrated-hypophysectomized mice. Such extragonadal effects of G100-fr.3 were also observed in intact female mice. These results suggest that certain LH isoforms may have extragonadal actions involving the kidney and liver.

During the period 1952 to 1976 at Vanderbilt University Hospital 119 patients with pituitary-dependent hypercortisolism or Cushing's disease were studied. The less severe cases, which constitute a majority, were treated by pituitary irradiation with endocrinologic cure or improvement in two-thirds of the treated patients. Bilateral total adrenalectomy was reserved for the most severe cases and for failures of pituitary irradiation. In 29 patients with total bilateral adrenalectomy there was one postoperative death. Two of 28 survivors had incomplete relief of hypercortisolism and required additional therapy for its control. One patient with recent operation is improved and another with early improvement died suddenly at home three months after operation. The 24 other adrenalectomized patients, followed 6 months to 20 years, were considered endocrinologic cures of Cushing's disease. One patient in the group who had not received pituitary irradiation developed signs of expanding pituitary tumor after adrenalectomy (Nelson's syndrome) with satisfactory response to radiation therapy.

To determine the usefulness of conventional pituitary irradiation in childhood Cushing's disease, we reviewed the results of this treatment in 15 patients. Twelve were cured (mean plasma cortisol of less than 10 microgram per deciliter and 24-hour urinary 17-hydroxycorticosteroid excretion of less than 7 mg per gram of creatinine) within 18 months, and 10 of the 15 were cured within nine months. Three failures required bilateral adrenalectomy. Growth resumed in 12, with adult heights of 156 to 166 cm. Sexual development proceeded normally in all 15, with normal secondary sexual characteristics and sexual function, and demonstrated fertility in four married adults. Intellectual function appeared normal. Basal and stimulated hormone levels were normal, except for subnormal (5 ng per milliliter or less) growth hormone levels after hypoglycemia in one of 12 patients. There were no complications of therapy and no progressive pituitary enlargement or hyperpigmentation. Pituitary irradiation is safe and effective therapy for childhood Cushing's disease.

This study was designed to assess the response of cyclic AMP to "endogenous" hormonal stimulation resulting from insulin-induced hypoglycemia. Insulin was administered to four normal subjects and four adrenalectomized patients. Hypoglycemia resulted in four-fold increases in plasma cyclic AMP. This response is thought to be secondary to beta-adrenergic stimulation for the following reasons: (1) the response was absent in adrenalectomized, cortisol-treated subjects; (2) it was abolished by propranolol; and (3) urinary excretion of cyclic AMP did not reflect the rise in plasma cyclic AMP.

The development of a uniquely sensitive and specific antiserum to AI has led to the establishment of a radioimmunoassay capable of detecting 7.5 pg of AI per milliliter of plasma. Due to its sensitivity this assay permits the measurement of circulating levels of AI, obviating many of the controversial aspects of previously described AI assays which all required either an incubation step at 37 degrees C to allow renin to catalyze the formation of sufficient AI or an extraction procedure to concentrate sufficient peptide to make quantification feasible. Since the sensitivity of this assay also depends upon the availability of very pure trace, a method is described for preparing monoiodinated 125I-AI of specific activity greater than 1000 microCi/microgram. To demonstrate the versatility and sensitivity of this assay, changes in circulating AI levels in response to physiologic stimuli were measured. Blood samples were obtained from 88 subjects from the inferior vena cava below the renal veins in both the supine and upright positions. Values ranged from 12 to 1990 pg/ml of plasma. Eighty-five of the 88 displayed a rise in the AI level during an upright tilt, the mean for the group increasing from 220 to 385 pg/ml of plasma. Three subjects had samples drawn simultaneously from the inferior vena cava and a peripheral artery and/or vein. The amounts of AI in all three sampling locations were essentially the same. Seventeen patients with essential hypertension underwent an infusion of 1.5 L of normal saline, and circulating AI levels were determined before and 120 and 150 min after the start of the infusion. All 17 experienced suppression of their AI levels, the mean for the group at 0, 120 and 150 min being 177, 55, and 50 pg/ml of plasma, respectively. Circulating AI correlated well (r = 0.87009) with plasma renin activity in 226 samples from the renal veins and inferior vena cava from individuals with hypertension of various etiologies.

Both pregnenolone and 17-OH-pregnenolone were found to be higher in the plasma of patients with poorly controlled congential adrenal hyperplasia than in normal subjects. The plasma levels of these precursor steroids were significantly correlated with urinary 17-ketosteroid and pregnanetriol excretion and with plasma testosterone. The mechanism where by plasma pregnenolone and 17-OH-pregnenolone levels are elevated in patients with 21-hydroxylase deficiency is unknown, but the phenomenon of product inhibition is suggested as a possible explanation. As 17-OH-pregnenolone in plasma is almost entirely of adrenal origin, its measurement promises to be useful in the management of patients with congenital adrenal hyperplasia. Acute stimulation with ACTH caused negligible changes in the plasma levels of pregnenolone and 17-OH-pregnenolone and failed to distinguish between overly, appropriately, and under-treated patients. However, following repeated stimulation with repository ACTH, the steroid levels rose. These findings indicate limited adrenal responsiveness to ACTH following chronic glucocorticoid treatment of congenital adrenal hyperplasia, even in under-treated patients, and suggest that normal precursor steroid levels in plasma and normal 17-ketosteroid and pregnanetriol excretion can only be achieved by the suppression of total steroidogenesis to less than that occurring in normal subjects.

The blood pressure elevation of primary aldosteronism is caused by excessive production of the known mineralocorticoid, aldosterone. The blood pressure elevation of low-renin essential hypertension may also be caused by mineralocorticoid excess, but which which mineralocorticoid is responsible is uncertain. Normal levels of aldosterone, found in this disorder despite suppressed plasma renin, and the presence of an unknown mineralocorticoid have been hypothesized to explain low-renin essential hypertension. We contrasted the blood pressure responses and changes in aldosterone seen in patients with low-renin essential hypertension and primary aldosteronism during treatment with two adrenal enzyme inhibitors. The results demonstrate the similarity between decrease in blood pressure and in aldosterone during early adrenal inhibition in both primary aldosteronism and in low-renin essential hypertension. During treatment with a distal adrenal blocker, patients with primary aldosteronism demonstrated decreases in both aldosterone and blood pressure, whereas patients with low-renin essential hypertension showed a decrease in aldosterone without significant change in blood pressure. This suggested that aldosterone was not the major mineralocorticoid responsible for low-renin essential hypertension. Unknown mineralocorticoid excretion decreased (along with blood pressure) during early inhibition but failed to decrease (along with blood pressure) during late inhibition at a time when aldosterone excretion decreased. This suggests that unknown mineralocorticoids play significant roles in the blood pressure elevation of low-renin essential hypertension.

The possibility that dopamine may play a role in the in vivo control of aldosterone production in man was suggested to us by reports from others; (a) that bromocriptine, a dopaminergic agonist, inhibits the aldosterone response to diuresis and to the infusion of angiotensin or ACTH; and (b) that metaclopramide, a dopamine blocking agent, causes elevations in plasma aldosterone levels. To determine whether such effects were direct or indirect, we examined the action of dopamine on aldosterone biosynthesis in isolated, bovine adrenal cells. Dopamine significantly inhibits the aldosterone response to angiotensin (P < 0.001), but does not influence basal aldosterone biosynthesis. It has previously been reported that angiotensin stimulates both the early and late phases of aldosterone biosynthesis. The present experiments demonstrated that the enhancing effect of angiotensin on the conversion of deoxycorticosterone to aldosterone (late phase of aldosterone biosynthesis) was almost completely inhibited by dopamine (P < 0.001). A significant inhibitory effect of dopamine (10 nM) was seen even when aldosterone biosynthesis was stimulated by a grossly supraphysiological concentration of angiotensin II (10 muM). However, these studies did not demonstrate any direct effect of dopamine on the early phase of aldosterone biosynthesis (cholesterol to pregnenolone) basally or when stimulated, or on the late phase of aldosterone biosynthesis under basal conditions. These in vitro studies suggest a direct inhibitory role for dopamine on the late phase of aldosterone biosynthesis, which may account for the in vivo inhibition of the aldosterone response to angiotensin in subjects treated with a dopaminergic agent.

The effect of insulin-induced hypoglycemia upon plasma renin activity (PRA) was assessed in 4 normal volunteers, 4 adrenalectomized patients and 10 patients with various pituitary hormone deficiences. Significant increases in PRA were observed in all three groups. The PRA responses to hypoglcemia could be blocked by propranolol, and appeared to be potentiated by theophyline. It is concluded that sympathetic reflex stimulation, not adrenal-dependent and not pituitary-dependent, is the major mechanism for this phenomenon in man and that this adrenergic effect may be mediated by cyclic AMP.

Mineralocorticoid activity of several delta4-3-ketosteroids and their 5alpha-dihydro analogs were evaluated by bioassay using urinary Na:K ratio of adrenalectomized rats as an index of mineralocorticoid activity. Among delta4-3-ketosteroids, aldosterone, 11-deoxycorticosterone, corticosterone, cortisol, 11-dehydrocorticosterone, and cortisone showed mineralcorticoid activity with aldosterone, the most potent of the series, showing virtually maximum activity at a dose of 0.25 microgram/rat. 5alpha-Dihydroaldosterone and 5alpha-dihydro-11-deoxycorticosterone possessed distinct mineralcorticoid activity, albeit less than aldosterone and 11-deoxycorticosterone. 5alpha-Dihydrocorticosterone, 5alpha-dihydrocortisol, 5alpha-dihydro-11-dehydrocorticosterone, and 5alpha-dihydrocortisone did not show mineralocorticoid activity in doses up to 100 microgram/rat. It is concluded that reduction of the 4.5 double bond diminishes mineralocorticoid activity of delta4-3-ketosteroids. Nevertheless, 5alpha-dihydroaldosterone has distinct mineralocorticoid activity with potency of 1.8% of that of aldosterone and approximately the same as that of 11-deoxycorticosterone.