Mechanisms of dexamethasone-induced hypertension

Abstract

Adrenocortical steroids with predominant glucocorticoid activity, both naturally-occurring and synthetic, have long been recognised as a cause of hypertension. Models of glucocorticoid-induced hypertension (GC-HT) in the rat such as adrenocorticotrophic hormone-induced hypertension (ACTH-HT) and dexamethasone-induced hypertension (DEX-HT) are well-characterised, although the mechanisms contributing to hypertension are less well-understood. Previous studies have shown that ACTH-HT is associated with increased renal vascular resistance, nitric oxide deficiency and oxidative stress. The latter was shown to be linked to the NAD(P)H oxidase but not the xanthine oxidase pathways. As there were proven differences in the pathogenesis of these two models of GC-HT, mechanisms of ACTH-HT cannot be assumed in DEX-HT. The main aim of this project was to evaluate the mechanisms of DEX-HT, namely the haemodynamic mechanisms and the role of oxidative stress. The role of {u03B2}-adrenergic receptor blockade was also evaluated. In some studies, experiments on both dexamethasone (DEX)- and ACTH-HT were conducted for comparison. DEX (10-20 {u03BC}g/rat/day) raised blood pressure in rats without significant metabolic side effects such as precipitous weight loss. The haemodynamic experiments showed that DEX-HT in rats was associated with increased total peripheral resistance and decreased total peripheral conductance, although these were not critical features for the production of DEX-HT. This project showed that the xanthine oxidase pathway and mitochondria were not the major source of superoxide contributing to oxidative stress in DEX-HT. Mitochondrial superoxide, evaluated using a novel mitochondrial specific fluorogenic probe (mito-hydroethidine) via flow cytometry designed for this purpose, was also shown in this project not to playa major role in ACTH-HT in rats. The arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid, which is increased by nitric oxide deficiency and known to cause oxidative stress and exacerbate nitric oxide deficiency, also did not playa significant role in the pathogenesis of DEX-HT. Propranolol, both a beta adrenergic receptor blocker and lipid peroxidation inhibitor, was not effective in preventing GC-HT. In conclusion, an increase in total peripheral resistance and nitric oxide-redox imbalance appear to be features of DEX-HT in the rat although the exact mechanism by which DEX raises blood pressure in human remains incompletely understood. Further studies exploring 1) the differences in mechanisms between naturally-occuring and synthetic glucocorticoids and 2) the relevance of oxidative stress and nitric oxide-redox imbalance in human GC-HT are important in advancing our understanding in this form of hypertension. Show more