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. Ingestion of dexamethasone by rats telemetrically instrumented increased blood pressure progressively over 7 days. Plasma concentrations of Na(+) and K(+) and urinary Na(+) and K(+) excretion remained constant, excluding a mineralocorticoid-mediated mechanism. Plasma NO(2)(-)/NO(3)(-) (the oxidation products of NO) decreased to 40%, and the expression of endothelial NO synthase (NOS III) was found down-regulated in the aorta and several other tissues of glucocorticoid-treated rats. The vasodilator response of resistance arterioles was tested by intravital microscopy in the mouse dorsal skinfold chamber model. Dexamethasone treatment significantly attenuated the relaxation to the endothelium-dependent vasodilator acetylcholine, but not to the endothelium-independent vasodilator S-nitroso-N-acetyl-D,L-penicillamine. Incubation of human umbilical vein endothelial cells, EA.hy 926 cells, or bovine aortic endothelial cells with several glucocorticoids reduced NOS III mRNA and protein expression to 60-70% of control, an effect that was prevented by the glucocorticoid receptor antagonist mifepristone. Glucocorticoids decreased NOS III mRNA stability and reduced the activity of the human NOS III promoter (3.5 kilobases) to approximately 70% by decreasing the binding activity of the essential transcription factor GATA. The expressional down-regulation of endothelial NOS III may contribute to the hypertension caused by glucocorticoids.
Wallerath
T
T
Department of Pharmacology, Johannes Gutenberg University Medical School, 55101 Mainz, Germany.
Witte
K
K
Schäfer
S C
SC
Schwarz
P M
PM
Prellwitz
W
W
Wohlfart
P
P
Kleinert
H
H
Lehr
H A
HA
Lemmer
B
B
Förstermann
U
U
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D014157:Transcription Factors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D017931:DNA Primers; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D014157:Transcription Factors; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat