Dexamethasone inhibits the inducible bioconversion of glyceryl trinitrate to nitric oxide.
The aim of this study was to assess the effects of dexamethasone (DEX) on the inducible bioconversion of glyceryl trinitrate (GTN) into nitric oxide in cultured smooth muscle cells, endothelial cells, and the J774 macrophage cell line as well as in vivo and ex vivo in rats either untreated or pretreated with Escherichia coli lipopolysaccharide. In vitro, an increased bioconversion of GTN to nitrite and an elevation of cyclosine guanosine 3,5;-monophosphate (cGMP) levels occurred after treatment with lipopolysaccharide (LPS) (0.5 microg/ml, 18 h). This effect was ablated by co-incubation with DEX (10 microM, 18 h). Rats treated with an intraperitoneal (IP) injection of LPS (4 mg/kg) 18 h beforehand showed enhanced hypotensive responses to GTN (1 mg/kg, intravenously [IV]) and this was prevented when DEX (4 mg/kg, IP) was given together with LPS. Progesterone (50 mg/kg, IP) had no effect on GTN-induced hypotensive response. Conversely, exposure of rat aortic strips obtained from animals pretreated with LPS produced an enhanced vasorelaxant response in LPS-treated rats. Also, this effect was inhibited by pretreatment with DEX. Thus, the induction of the pathway leading to the formation of nitric oxide from GTN is blocked by DEX both in vitro and in vivo, and this may represent a useful tool in the assessment of the enhanced bioconversion of organic nitrates into nitric oxide occurring via inflammatory mechanisms.
Mollace
Vincenzo
V
Faculty of Pharmacy, University of Catanzaro Magna Graecia, Complesso Nini' Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy. mollace@libero.it
Muscoli
Carolina
C
Iannone
Michelangelo
M
Palma
Ernesto
E
Rotiroti
Domenicantonio
D
Romeo
Francesco
F
Nisticò
Robert
R
Salvemini
Daniela
D
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D005996:Nitroglycerin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D014664:Vasodilation / Q000187:drug effects
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D003907:Dexamethasone; D005996:Nitroglycerin; D006152:Cyclic GMP