Hemoglobin increases endothelin-1 in endothelial cells by decreasing nitric oxide

We determined whether ferrous hemoglobin increases endothelin-l (ET-1) secr etion from bovine cerebral artery endothelial cells and the mechanisms invo lved. Exposure of endothelial cells to hemoglobin caused dose-dependent inc reases in pre-proET-1 mRNA and peptide. The increase in ET-1 peptide was in hibited by cycloheximide or actinomycin D whereas only cycloheximide decrea sed basal ET-1 release. N-G-nitro-L-arginine significantly increased ET-1 c oncentration and reduced hemoglobin stimulation of ET-1 release. 8-Bromo-cG MP did not alter basal ET-1 concentration but suppressed hemoglobin-induced ET-1 production. Methemoglobin and S-nitrosylated methemoglobin were less potent inducers of ET-1 release. In summary, hemoglobin increases ET-1 in c erebral endothelial cells by mechanisms that involve transcription and tran slation. Nitric oxide production inhibits ET-1 production. Ferrous hemoglob in increases ET-1 by binding nitric oxide and abolishing this inhibitory pa thway although other mechanisms are involved since N-G-nitro-L-arginine red uces hemoglobin-induced ET-1 release. (C) 2001 Academic Press.