Brownie, Alexander Charles

2019-02-15T14:32:46Z

2019-02-15T14:32:46Z

1981

Four animal models of experimental hypertension characterized by a dysfunctional adrenal cortex are related to increased secretion of the potent mineral ocorticoid and hypertensinogenic agent, 11-deoxycorticosterone (DOC). This increase is due to a reduction in the activity of steroid 113- and 18-hydroxylase, leading to decreased production of corticosterone and 18-hydroxy-DOC.

In adrenal regeneration hypertension, there is a differential regeneration of cholesterol side chain cleavage and steroid 118/18-hydroxylase. Regenerating adrenals have normal or increased cholesterol side chain cleavage activity, coupled with decreased 11ß/18-hydroxylase activity. These changes were measured by determining enzyme activities and substrate interactions with relevant cytochrome P450 enzymes. Cholesterol association with cytochrome P450scc and DOC association with cytochrome P450₁₁ß , were assessed by light absorption and electron spin resonance spectroscopy. Measurement of corticosteroid levels in blood indicate that hypersecretion of DOC is involved in the pathogenesis of adrenal regeneration hypertension. Furthermore, the importance of studying animals under quiescent conditions and of taking measurements at the high as well as low point of the circadian rhythm are demonstrated.

In studies of androgen-induced hypertension, administered androgen or a metabolite, was shown to bind to the 118-hydroxylase form of adrenal mitochondrial cytochrome P450. This can decrease secretion of corticosterone and 18-hydroxy-DOC but increase DOC secretion. Androgen treatment clearly affects adrenal cortical cytochrome P450 levels. Since adrenal cholesterol side chain cleavage activity is increased in treated animals, more DOC is produced. This elevation in blood DOC levels is most easily demonstrated at the high point of the circadian rhythm of adrenal cortical activity

The mechanism of metopirone-induced hypertension involves the binding of the drug and its reduced metabolite to the 11ß-hydroxylase form of adrenal mitochondrial cytochrome P450. The resultant inhibition of steroid 11ß-hydroxylase is transient compared to that observed in androgen-treated animals. The accompanying increased blood DOC levels are also implicated in the development of hypertensive vascular disease.

The mammotropic pituitary tumour, MtTF4, which secretes large amounts of ACTH, prolactin and growth hormone, causes pronounced adrenal cortical hyperplasia. The hyperplastic adrenals have lower levels of adrenal mitochondrial cytochtome P450 and have reduced steroid 11 ß/18-hydroxylase activity. Blood DOC levels are higher than in controls. Hypertensive vascular disease precedes rapid deterioration in the health of the animals.

These models point to the role of adrenal cortical dysfunction in hypertension. In particular, a zona fasciculata-reticularis derived mineralocorticoid (DOC) seems to cause hypertension. The increase in DOC secretion in three of these models is related to alterations in the fine structure of zona fasciculata-reticularis mitochondria. These alterations are in turn correlated with changes in adrenal mitochondrial cytochrome P450. These findings are of interest in connection with the,, potential role of the adrenal cortex in low renin essential hypertension in man.

http://hdl.handle.net/1842/34919

The University of Edinburgh

Annexe Thesis Digitisation Project 2019 Block 22

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Adrenal cortical dysfunction in the pathogenesis of experimental hypertension

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