Tissue sensitivity to glucocorticoids in hypertension

116-Hydroxysteroid dehydrogenase catalyses the conversion of Cortisol to inactive cortisone. In kidney, the enzyme confers aldosterone-specificity on mineralocorticoid receptors by preventing their occupancy by Cortisol. The expression of 118dehydrogenase in many extra-renal sites suggests that it has a wide role in modulating Cortisol sensitivity. When renal 118-dehydrogenase is defective (as occurs in congenital deficiency and after inhibition of the enzyme by liquorice or carbenoxolone) cortisol-dependent mineralocorticoid excess and hypertension ensue. In this thesis I address the hypotheses that: (i) in addition to its role in the kidney, 118-dehydrogenase modulates Cortisol sensitivity in vascular smooth muscle; (ii) 11Bdehydrogenase is regulated physiologically by the hypothalamic-pituitary-adrenal axis; and (iii) deficiency of 1 lB-dehydrogenase, associated with increased Cortisol sensitivity either in kidney or in blood vessels, contributes to pathophysiology in other forms of hypertension, specifically ectopic ACTH syndrome and essential hypertension. I show that llB-dehydrogenase immunoreactivity and mRNA are localised to vascular smooth muscle cells in rats, and bioactivity is greater in resistance vessels than conduit arteries. In support of a diverse role for the enzyme in modulating vascular tone I demonstrate: (i) potentiation of vasoconstrictor sensitivity to Cortisol and thereby to noradrenaline in the forearm and dermis of men given enzyme inhibitors or congenitally deficient in llB-dehydrogenase; and (ii) attenuation of noradrenaline reactivity by glucocorticoids in rat aorta which is increased following in vitro carbenoxolone administration. By studying in vitro affinities of rat vascular 1 lB-dehydrogenase for its cofactors I demonstrate its similarity to the hepatic isoform of the enzyme, and distinguish it from that in kidney. Moreover, vascular but not renal 1 lB-dehydrogenase is induced by in vivo administration of glucocorticoids. By contrast, ACTH is without effect on 116dehydrogenase in adrenalectomised rats, but inhibits the peripheral conversion of Cortisol to cortisone in man. By selective venous catheterisation studies I confirm that the major site for this conversion is the kidney. Thus ACTH, in addition to stimulating Cortisol synthesis, may stimulate the secretion of an 1 lB-dehydrogenase inhibitor from the adrenal, and thereby increase renal sensitivity to Cortisol. In 9 patients with ectopic ACTH syndrome the ratio of plasma Cortisol to cortisone was higher than in 17 patients with other forms of Cushing's syndrome, and con-elated negatively with plasma potassium concentration. In patients with essential hypertension 1 lB-dehydrogenase activity (measured by the half life of (lla3H)cortisol) was deficient in 7 of 20 patients studied. These patients did not have evidence of mineralocorticoid excess. However, dermal vascular sensitivity to Cortisol, although not significantly correlated with 1 lB-dehydrogenase activity, was increased in the hypertensives. In conclusion, 1 lB-dehydrogenase deficiency may mediate hypertension by more than one mechanism. In ectopic ACTH syndrome inhibition of renal 1 lB-dehydrogenase allows Cortisol to activate mineralocorticoid receptors and induce the characteristic features of hypokalaemia and hypertension. By contrast, in essential hypertension llB-dehydrogenase deficiency is not associated with mineralocorticoid excess, but may underlie an increase in vasoconstrictor sensitivity to Cortisol. Thus the significance of defective enzyme-mediated receptor protection in clinical practice is confirmed.