In vitro stimulation of 25-hydroxycholecalciferol 1 alpha-hydroxylation by parathyroid hormone in chick kidney slices: evidence for a role for adenosine 3',5'-monophosphate.

We studied the effect of parathyroid hormone (PTH) on the in vitro conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] by kidney slices from vitamin D-deficient chicks. Bovine PTH (bPTH) stimulated 1,25-(OH)2D3 production at low concentrations, with maximal stimulation (65%) at a concentration of 25 ng/ml bPTH in the absence of theophylline. Higher concentrations of bPTH resulted in less stimulation. The addition of 5 mM theophylline to the incubation buffer decreased basal 1,25-(OH)2D3 production but potentiated the stimulation of 1,25-(OH)2D3 production by PTH. Maximal stimulation (170%) was observed with 2 ng/ml bPTH in the presence of theophylline. Maximal stimulation of cAMP production by the kidney slices required 2- to 3-fold larger concentrations of bPTH. However, cAMP by itself stimulated 1,25-(OH)2D3 production, with maximal stimulation (70%) at 10(-7)-10(-5) M cAMP. We conclude that stimulation by PTH of 1,25-(OH)2D3 production can be potentiated by theophylline and mimicked by cAMP. However, such stimulation occurs at PTH concentrations lower than that required for optimal stimulation of adenylate cyclase activity.

Prolactin but not growth hormone stimulates 1,25-dihydroxyvitamin D3 production by chick renal preparations in vitro.

We studied the effect of PRL from two species (bovine and turkey) and GH from two species (bovine and turkey) on 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] production by two whole cell preparations from vitamin D-deficient chick kidneys (slices and tubules). We observed that 8 ng/ml turkey PRL stimulated 1,25(OH)2D3 production by renal tubules and slices. Ovine PRL had a similar effect on 1,25(OH)2D3 production but at higher concentrations. In contrast, neither bovine GH nor turkey GH stimulated 1,25(OH)2D3 production appreciably at doses up to 1000 ng/ml. The effect of PRL on 1,25(OH)2D3 production by renal tubules required a 3-h preincubation, although its effect on 1,25(OH)2D3 production by renal slices was immediate. We conclude that PRL, but not GH, directly stimulates 1,25(OH)2D3 production by the chick kidney.

The constant plasma 18-hydroxycorticosterone to aldosterone ratio: an expression of the efficacy of corticosterone methyloxidase type II activity in disorders with variable aldosterone production.

Aldosterone and 18-hydroxycorticosterone (18-OHB) are produced by the adrenocortical zona glomerulosa. Under normal conditions, plasma 18-OHB levels parallel and are influenced by the same trophic factors that regulate aldosterone production. To evaluate corticosterone-methyl-oxidase II activity, the final step of aldosterone biosynthesis, in conditions associated with chronic derangements of the pituitary-adrenal and/or renal-adrenal axis, we measured the plasma 18-OHB to aldosterone ratio, cortisol, PRA or plasma renin concentration, and potassium (K) in 104 such patients and 15 normal subjects. The 18-OHB to aldosterone ratios in the pituitary-adrenal group were not significantly different from normal regardless of elevated or reduced ACTH and/or cortisol levels [patients with Cushing's syndrome, 3.55 +/- 0.68 (+/-SE); ACTH deficiency, 2.03 +/- 0.34; 21-hydroxylase deficiency, 3.09 +/- 0.23; normal subjects, 2.50 +/- 0.15]. The renal-adrenal group also had normal ratios regardless of plasma renin concentration and K levels [patients with aldosterone-producing adenomas, 2.85 +/- 0.15; idiopathic hyperaldosteronism, 2.14 +/- 0.19; salt-losing nephropathy, 3.06 +/- 0.54; Bartter's syndrome, 2.89 +/- 0.20; isolated (hyporeninemic) hypoaldosteronism, 3.20 +/- 0.39]. Only in patients with 17 alpha-hydroxylase deficiency (230.1 +/- 118.6) was the ratio abnormally high. Chronic perturbations of aldosterone production by ACTH, the renin-angiotensin system, and/or K did not alter this last step of aldosterone biosynthesis (corticosterone-methyloxidase II), as defined by their plasma concentrations. Any influence of these trophic factors must be proximal to the site of 18-OHB production.

Effect of sulfonylurea therapy and plasma glucose levels on hemoglobin A1c in type II diabetes mellitus.

It is well known that hemoglobin A1c reflects plasma glucose concentrations in patients with diabetes mellitus. To examine hemoglobin A1c and plasma glucose relationships in sulfonylurea-treated patients, 25 patients with well-controlled type II diabetes (fasting plasma glucose 128 +/- 6 mg/dl, hemoglobin A1c 7.6 +/- 0.5 percent) were evaluated in a double-blind study. This study was divided into two phases (periods I and II). During period I each patient was given a diet plus a placebo and was followed every two weeks until the mean of two consecutive plasma glucose determinations was more than 50 mg/dl above the initial plasma glucose concentration obtained while the patient was taking sulfonylurea. At that point each patient was switched in a double-blind fashion to either diet plus a placebo or diet plus tolazamide. Fasting plasma glucose concentrations increased to 178 +/- 9 mg/dl (p less than 0.005) for all patients by week 2 of period I. The increase in hemoglobin A1c concentration was seen to lag behind the increasing fasting plasma glucose concentration by four to six weeks. Fasting plasma glucose and hemoglobin A1c concentrations returned to values indistinguishable from initial values in patients who were given tolazamide and who responded to it. A positive correlation was noted when the hemoglobin A1c concentration was compared with the fasting plasma glucose concentration measured four to six weeks previously.

Adrenocorticotropin inhibition of mineralocorticoid hormone production.

1. Adrenocorticotropin (ACTH)-induced steroidogenesis, obtained by continuous administration of ACTH for 3 days, produces in man (a) sustained elevations of plasma deoxycorticosterone and cortisol concentrations, (b) transient elevations of plasma aldosterone and 18-hydroxycorticosterone concentrations that return to near-control values, and (c) brisk initial increases in plasma 18-hydroxydeoxycorticosterone and corticosterone concentrations that fall to 20-68% of peak values 30 h thereafter. 2. Dexamethasone (8 mg/day, orally) treatment for 2 days in man permits a greater postural increase in plasma aldosterone and 18-hydroxycortisone concentrations. A dampening effect of ACTH is suggested. 3. An ACTH-initiated inhibition of 11 beta- and 18-hydroxylation is proposed to be operative in regulation of mineralocorticoid hormones.

Use of computed tomography in diagnosing the cause of primary aldosteronism.

We performed computed tomography (CT) in 22 consecutive patients with primary aldosteronism to evaluate the usefulness of this technique in diagnosing and locating aldosterone-producing adenomas. Sixteen patients had severe hypokalemia, hyperaldosteronism, and elevated plasma levels of 18-hydroxycorticosterone suggestive of an adenoma. In 12 of these 16, a unilateral adrenal mass was demonstrated clearly, and in all 11 who had surgery in adenoma was confirmed. In the other four patients in this group, one adrenal gland was normal and the other was either not seen adequately or had minor abnormalities that could not be definitely classified; an adenoma was found in the poorly visualized gland in each of the two patients who had surgery. The remaining six patients, who had milder biochemical abnormalities suggestive of idiopathic hyperaldosteronism, had bilateral adrenal enlargement or normal-appearing glands on scan and were not surgically explored. We conclude that CT scans, together with appropriate biochemical measurements, are useful in diagnosing and locating aldosterone-producing adenomas.