GLUCOCORTICOID-DEPENDENT HYPERTENSION

Glucocorticoid (GC) excess (Cushing's syndrome) is associated with hypertension in at least 70% of patients (in our series 89/130), independently of the subtype (pituitary or adrenal) and the duration, but not of the age of the patients. Cardiovascular damage is quite frequent in hypertensives, but is sometimes also present in normotensives. The mortality of patients with Cushing's syndrome is four times that of the general population when matched for age and sex, and much of this excess mortality is caused by cardiovascular disease. Hypertension remits in most of the patients after successful treatment, but may persist in some. Hypertension also occurs in 20% of patients treated with GC orally. The type of hypertension is independent of salt uptake, can not be controlled by spironolactone but is inhibited by a GC antagonist such as RU486. Experimentally-induced hypertension with oral cortisol (F) is associated with a rise in cardiac output, a fall in calculated total peripheral resistance, an increased forearm vascular responsiveness to exogenous norepinephrine, but no change in overall sympathetic tone, or in norepinephrine reuptake. The increased pressor responsiveness is probably due to local postsynaptic effector mechanisms in the resistance vessels, which could be important in phasic increases in neuronally mediated constrictor responses. Both in patients with Cushing's syndrome and in those on chronic GC treatment, the circadian blood pressure variations are absent or reversed. This may contribute to the deleterious effects of the GC excess on blood vessels. The vascular effects of the GC may be mediated by the activation of specific cardiovascular receptors, by modulating vascular transport systems, or by altered catecholamine or prostaglandin metabolism. GC may also act as mineralocorticoids (MC): in fact type 1 MC receptors are unable, in vitro, to distinguish between aldosterone and cortisol. The specificity-conferring mechanism of typical target organs for MC (e.g. kidney)-is thought to be due to the action of local 11-beta-hydroxysteroid dehydrogenase, which converts F to biologically inactive cortisone (E). When the activity of the enzyme is impaired (syndrome of apparent MC excess, liquorice or carbenoxolone administration), F acts as a MC and MC-hypertension with hypokalemia occurs. Furthermore, in the syndrome of dexamethasone-suppressible hyperaldosteronism, an abnormal elevation of 18-hydroxy- or 18-oxo-F (possibly as a consequence of gene conversion between the 2 genes which encode for 11-beta-hydroxylase in the zona fasiculata and glomerulosa, respectively) may contribute to the circulating MC activity, that results higher than expected by the measured levels of aldosterone, deoxycorticosterone and F.