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  • Author: J. Alaghband-Zadeh x
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S. C. J. READER, J. ALAGHBAND-ZADEH, J. R. DALY and W. R. ROBERTSON

Plasma ACTH and corticosteroid levels were measured in normal subjects during constant infusion of either 0·9% (w/v) NaCl solution or cortisol, and during insulin-induced hypoglycaemia. During infusions of 0·9% NaCl solution the secretion of ACTH and corticosteroids was episodic. Fast, rate-sensitive, negative feedback inhibition of ACTH secretion was observed during cortisol infusions, when the corticosteroid levels were within the physiological range (200–750 nmol/l) and were rising at a rate of between 5 and 10 nmol/l per min for 30 min or longer. When plasma corticosteroid levels were in a steady state, the initial fast feedback effects were abolished and ACTH secretion resumed. However, this recovery of ACTH secretion was not seen when the corticosteroid levels were persistently above 800 nmol/l. It appears that corticosteroid-induced negative feedback in man may be both rate- and level-sensitive. During insulin stress tests ACTH secretion fell at a time when the plasma corticosteroid level was rising rapidly (> 5 nmol/l per min) despite persistent hypoglycaemia.

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J. A. Millett, S. M. Holland, J. Alaghband-Zadeh and H. E. de Wardener

ABSTRACT

The plasma of normal man and the rat, and an acetone extract of hypothalamus from the rat, have an ability to inhibit Na-K-ATPase which is related directly to salt intake. The ability of the plasma to inhibit Na-K-ATPase is raised in essential hypertension.

The ability of plasma and of an acetone extract of hypothalamus from six spontaneously hypertensive (SHR) rats and six normotensive control (WKY) rats to inhibit Na-K-ATPase of fresh guinea-pig kidney was studied using cytochemical bioassay techniques. With a validated assay, which measures the capacity of biological samples to stimulate glucose-6-phosphate dehydrogenase (G6PD) as an index of their capacity to inhibit Na-K-ATPase, the mean G6PD-stimulating ability of the plasma from the SHR and the WKY rat was 772·3 ± 48·1 units/ml and 12·5 ± 2·6 units/ml respectively (P < 0·01) and of the hypothalamic extracts it was 2·2 ± 1·7 × 108 and 4·5 ± 1·8 × 104 units/hypothalamus (P < 0·01). With a semi-quantitative cytochemical assay, which measures Na-K-ATPase activity directly, plasma and an acetone extract of hypothalamus from the spontaneously hypertensive rat had much greater capacities to inhibit Na-K-ATPase than plasma and extract from the WKY rat.

These raised levels of Na-K-ATPase inhibitory activity in the plasma of the SHR rat are similar to the highest values found in the plasma of patients with essential hypertension. The results suggest that the substance responsible for the increased capacity of the plasma to inhibit Na-K-ATPase may originate from the hypothalamus and that it may, in part, be involved in the mechanisms which induce the rise of arterial pressure in inherited forms of hypertension.

J. Endocr. (1986) 108, 69–73

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J. Alaghband-Zadeh, S. Fenton, K. Hancock, J. Millettt and H. E. de Wardener

Acetone extracts from a variety of rat tissues were tested for their ability to stimulate renal glucose-6-phosphate dehydrogenase (G6PD) activity at 2 min in an in-vitro cytochemical assay which is a marker of the sodium potassium-dependent adenosine triphosphatase (Na+-K+-ATPase) inhibiting activity. Extracts of the hypothalamus were the only ones found to be active in this system. Acetone extract of hypothalamus also inhibited renal Na+-K+-ATPase activity in vitro. The G6PD-stimulating activity from one hypothalamus was about 10000 to 100 000 times greater than that of 1 ml plasma. The G6PD-stimulating activity of hypothalamic extracts from rats which had been on a high sodium intake for 4 weeks were approximately 150 times more active than those obtained from rats which had been on a low sodium diet. The G6PD-stimulating activity of the corresponding plasma was sixfold more active. These findings suggest that a circulating sodium transport inhibitor(s) may be secreted from the hypothalamus.

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J. A. Millett, S. M. Holland, J. Alaghband-Zadeh and H. E. de Wardener

ABSTRACT

Some physicochemical properties of partially purified hypothalamic material from the spontaneously hypertensive rat, and of plasma from man and the rat, have been characterized using a validated cytochemical bioassay which measures the ability of biological fluids to stimulate fresh guinea-pig kidney glucose-6-phosphate dehydrogenase (G6PD) after 2 min of exposure to the test substance, as an indication of their ability to inhibit Na+/K+ adenosine triphosphatase (Na+/K+-ATPase) after 4–6 min of exposure.

The G6PD-stimulating activity of both hypothalamic extract and plasma is soluble in water and insoluble in chloroform. During electrophoresis the activity from both sites appears in the same fractions and travels considerably further than lysine. After high-pressure liquid chromatography the activity of hypothalamic extract appears in a discreet fraction which does not absorb u.v. light. The activity of both the hypothalamic extract and plasma survives boiling and acid hydrolysis, but is substantially inhibited by prior incubation with digoxin antibody. From ultrafiltration studies, the substance responsible for the ability to stimulate G6PD appears to have a molecular weight of less than 500. The G6PD-stimulating activity of hypothalamic extracts was destroyed by ashing and by base hydrolysis. The ability of plasma of high activity to stimulate G6PD is considerably increased by incubating at 37 °C for 15 min and destroyed by incubation for 45 min.

It is concluded that these and several other previously noted similarities suggest that the cytochemically assayable Na+/K+-ATPase-inhibiting/G6PD-stimulating activity in the plasma and hypothalamus may be due to the same ouabain-like substance.

J. Endocr. (1987) 112, 299–303

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S. Fenton, E. Clarkson, G. MacGregor, J. Alaghband-Zadeh and H. E. de Wardener

A highly sensitive cytochemical method for the assay of the ability of plasma and extracts of human urine to stimulate renal glucose-6-phosphate dehydrogenase (G6PD) activity in vitro is described. In the proximal convoluted tubules there was a linear increase of G6PD activity with the logarithm of concentration of a highly purified natriuretic extract from normal human urine (0·384–384 ng active material/l) which was used as a standard. The stimulation of G6PD obtained with dilutions of normal human plasma was parallel to that produced by the standard. The sensitivity of the assay permitted the measurement of as little as 0·384 ng active material/l of the natriuretic extract (0·001 units/ml) and dilutions of 1/10 000 could be detected using normal human plasma. The mean ± s.e.m. index of precision was 0·068± 0·003 (n = 9).

It is known that inhibition of sodium potassium-dependent adenosine triphosphatase (Na+-K+-ATPase) is associated with a rise in G6PD activity. We have confirmed this observation by demonstrating that ouabain, a potent inhibitor of Na+ -K+-ATPase, stimulates renal G6PD activity in our assay and that natriuretic extract, human plasma and ouabain stimulated renal G6PD activity in vitro and simultaneously inhibited renal Na+-K+-ATPase activity in vitro.

The plasma from 12 normal subjects (five of whom were previously shown to inhibit renal Na+-K+-ATPase activity in vitro in a manner related to sodium intake) stimulated renal G6PD activity in vitro, and this activity was also directly related to sodium intake.

It is suggested that the change in the capacity of plasma to stimulate renal G6PD activity in vitro is a marker of the concentration of a circulating sodium transport inhibitor.