Biomedical subjects
G W Liddle
Publications and source records attributed to G W Liddle.
Surgical experience with Cushing's disease.
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.
The C19-mineralocorticoids in hypertension.
The excretion rates of the C19-mineralcorticoids, 16beta-hydroxy-DHEA and 16-oxo-androstenediol, were measured in subjects with low-renin essential hypertension and toxemia of pregnancy. C19-mineralocorticoid excretion in low-renin essential hypertension ranged from 70-790 microgram per day. No significant difference in 16beta-hydroxy-DHEA and 16-oxo-androstenediol excretion was found between these subjects and normal controls. Subjects with toxemia of pregnancy excreted between 350 and 2500 microgram per day of these steroids. There was no significant difference between toxemic and normal pregnancy. Thus, 16beta-hydroxy - DHEA and 16-oxo-androstenediol probably do not play an important role in either low-renin essential hypertension or toxemia of pregnancy.
Plasma pregnenolone and 17-OH-pregnenolone in patients with adrenal tumors, ACTH excess, or idiopathic hirsutism.
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.
Saralasin infusion in the recognition of renovascular hypertension.
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.
Are there unknown mineralocorticoids in low-renin essential hypertension?
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.
Contrasting effects of hypoglycemia on plasma renin activity and cyclic adenosine 3',5'-monophosphate (cyclic AMP) in low renin and normal renin essential hypertension.
Insulin-induced hypoglycemia previously has been shown to provoke a beta-adrenergic response that normally results in an increase in plasma renin activity (PRA). In our study, hypoglycemia induced definite increases in PRA in a group of five patients with normal renin essential hypertension but failed to do so in a group of six patients with low renin essential hypertension. In both groups, plasma cyclic adenosine 3',5'-monophosphate (cyclic AMP; cAMP) increased more than 2-fold during hypoglycemia, but the response in the low renin group was significantly less than that previously observed in normal subjects under the same conditions. Plasma cortisol increased to an equal extent in both groups of hypertensive patients during hypoglycemia. Infusion of the phosphodiesterase inhibitor, theophylline, resulted in definite increases of PRA in patients with normal renin hypertension but not in patients with low renin hypertension. Because changes in the level of plasma cAMP during hypoglycemia have been thought to reflect adrenal catecholamine release, our finding of a blunted increase in plasma cAMP during hypoglycemia in patients with low renin hypertension may suggest that there is a generalized alteration in adrenergic responsiveness in this condition.
Pregnenolone, 17-OH-pregnenolone, and testosterone in plasma of patients with congenital adrenal hyperplasia.
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.
Plasma 16 beta-hydroxydehydroepiandrosterone in normal and pathological conditions in man.
Plasma 16beta-hydroxydehydroepiandrosterone (16 beta-OH-DHEA) levels in normal subjects and patients with certain pathological conditions have been evaluated using radioimmunoassay of the steroid. Plasma 16 beta-OH-DHEA levels in normal subjects rose sharply during adolescence and then declined slowly throughout adult life: 192 +/- 54 (SE) pg/ml between 7 and 11 yrs., 395 +/- 22 pg/ml between 15 and 19 yrs, 330 +/- 29 pg/ml between 20 and 39 yrs., 291 +/- 35 pg/ml between 40 and 59 yrs., and 124 +/- 20 over 60 yrs. No significant difference was found between male and female subjects. Plasma 16 beta-OH-DHEA rose significantly (P less than 0.001) during ACTH stimulation, declined significantly (P less than 0.005) during dexamethasone suppression, declined significantly (P less than 0.05) during gonadal suppression, rose significantly (P less than 0.05) during gonadal stimulation and rose significantly (P less than 0.005) after the administration of WIN 24,540, an inhibitor of 3 beta-ol-dehydrogenase. The concentration of 16 beta-OH-DHEA in adrenal venous blood was higher than in inferior vena cava blood, but 16 beta-OH-DHEA in hepatic venous blood was not higher than 16 beta-OH-DHEA in arterial blood. It is inferred that 16 beta-OH-DHEA is secreted directly by the adrenal cortex and probably the gonads. Plasma 16 beta-OH-DHEA was elevated in normal pregnant women, pregnant women with toxemia, and in patients with Cushing's disease, ectopic ACTH-producing tumor, and congenital adrenal hyperplasia, but it was not elevated in patients with low-renin essential hypertension.
New mineralcorticoids in the syndrome of low-renin essential hypertension.
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Effect of hypoglycemia on extracellular levels of cyclic AMP in man.
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.
Effect of isoniazid on the protoplasmic viscosity in Mycobacterium tuberculosis.
The effect of isoniazid on the protoplasmic viscosity in the H37Ra strain of Mycobacterium tuberculosis was determined by using electron spin resonance spectroscopy and a small spin label tempone (2,2,6,6-tetramethylpiperidone-N-oxyl radical). Isoniazid (0.5 mug/ml) caused the internal cellular viscosity to increase gradually over the first 15 h of exposure from a rotational correlation time value (T(c)) of 2.4 x 10(-10) to 3.4 x 10(10) s and then decrease linearly to the control level after 27 h. These results could be interpreted to mean that isoniazid allows a continued and normal synthesis of the protoplasmic components while the rate of increase in the cell volume is reduced. A degradative process may begin after the initial 15-h exposure time, which would cause the reduction in the internal viscosity.
Evidence for a new mineralocorticoid in patients with low-renin essential hypertension.
Patients with low-renin essential hypertension have certain features consistent with excessive mineralocorticoid activity. Because known mineralocorticoids are normal in the majority of low-renin essential hypertension patients, an unknown mineralocorticoid was sought in the urine of such patients. Urine extracts from patients with low-renin essential hypertension were assayed for mineralocorticoid activity in adrenalectomized rats and found to contain more such activity than could be accounted for by the known mineralocorticoids in the extracts. The factor responsible for the unexplained mineralocorticoid activity was purfied and then identified by mass spectral analysis as 16beta-hydroxydehydroepiandrosterone (16beta-OH-DHEA). Synthetic 16beta-OH-DHEA was found to have a mineralocorticoid potency one-fortieth that of aldosterone in the rat bioassay. The mineralocorticoid effects of both the urine extracts and the synthetic steroid were blocked in the rat by spironolactone, a mineralocorticoid antagonist. A specific assay for 16beta-OH-DHEA was developed, and its level in the urine was found to be elevated in patients with low-renin essential hypertension.
Studies of the elevated extracellular concentration of cyclic AMP in uremic man.
This study was designed to elucidate the mechanism of elevation of plasma cyclic AMP in uremic man. Plasma cyclic AMP was measured in 15 normal subjects and in 18 patients with severe renal failure. In some members from both groups the kinetic parameters of the metabolism of extracellular cyclic AMP were measured. Plasma cyclic AMP was elevated from 23 nM in control subjects to 59 nM in uremic patients, regardless of the presence or absence of the kidneys or parathyroid glands. A single pass of uremic blood through a Kiil hemodialyzer decreased plasma cyclic AMP from 58 to 30 nM. The clearance of cyclic AMP by the dialyzer correlated directly with the blood flow passing through the machine. Hemodialysis for 6 h decreased plasma cyclic AMP levels in the systemic circulation by only 12%. Studies with tritiated cyclic AMP revealed a plasma clearance rate of 624 ml/min in normal subjects and of 344 ml/min in patients with uremia. Such a large decrease in plasma clearance rate cannot be explained by a failure of urinary excretion of cyclic AMP and suggests impairment of "metabolic clearance." In addition, the "plasms production rate" of cyclic AMP was 65% higher in patients with renal failure than in normal subjects. It is concluded that the elevation of plasma cyclic AMP in uremic man is due to a combination of: (a) lack of urinary excretion, (b) decreases metabolic clearance, and (c) increased production of plasma cyclic AMP.
Effect of insulin-induced hypoglycemia upon plasma renin activity in man.
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.
Effects of guanethidine and methyldopa on a standardized test for renin responsiveness.
A standardized test for renin responsiveness, employing the dual stimulus of upright posture and the loop diuretic furosemide, was applied to 19 hypertensive patients in the untreated state and during therapy with the antihypertensive agents guanethidine and methyldopa. During therapy with guanethidine, 6 of 10 patients with "low-renin essential hypertension" experienced elevations of plasma renin activity to levles ordinarily diagnostic of "normal-renin" hypertension (P less than 0.05), whereas methyldopa had no significant effect on plasma renin activity in either "low-renin" or "normal-renin" patients. It is suggested that methyldopa has a negligible influence on renin responsiveness when stimulated under the above conditions and that it may be used during assessment of plasma renin activity in hypertensive patients whose blood pressure is too severely elevated for temporary withdrawal of therapy.
The Distinguished Lecture. Is hypertension essential?
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Prolonged alteration of renin responsiveness after spironolactone therapy. A cause of false-negative testing for low-renin hypertension.
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