Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension

Hypertension is a side effect of systemically administered glucocorticoids, but the underlying molecular mechanism remains poorly understood. Ingestio n of dexamethasone by rats telemetrically instrumented increased blood pres sure progressively over 7 days. Plasma concentrations of Na+ and K+ and uri nary Na+ and K+ excretion remained constant, excluding a mineralocorticoid- mediated mechanism. Plasma NO2-/NO3- (the oxidation products of NO) decreas ed to 40%, and the expression of endothelial NO synthase (NOS III) was foun d down-regulated in the aorta and several other tissues of glucocorticoid-t reated rats. The vasodilator response of resistance arterioles was tested b y intravital microscopy in the mouse dorsal skinfold chamber model. Dexamet hasone treatment significantly attenuated the relaxation to the endothelium -dependent vasodilator acetylcholine, but not to the endothelium-independen t vasodilator S-nitroso-N-acetyl-D,L-penicillamine. Incubation of human umb ilical vein endothelial cells, EA,hy 926 cells, or bovine aortic endothelia l cells with several glucocorticoids reduced NOS III mRNA and protein expre ssion to 60-70% of control, an effect that was prevented by the glucocortic oid receptor antagonist mifepristone, Glucocorticoids decreased NOS III mRN A stability and reduced the activity of the human NOS III promoter (3.5 kil obases) to approximate to 70% by decreasing the binding activity of the ess ential transcription factor GATA. The expressional down-regulation of endot helial NOS III may contribute to the hypertension caused by glucocorticoids .