CONTRIBUTIONS OF NO SYNTHASE AND HEME OXYGENASE TO CGMP FORMATION BY CYTOKINE AND HEMIN TREATED BRAIN CAPILLARY ENDOTHELIAL-CELLS

Two mechanisms contribute to cGMP formation by soluble guanylyl cyclas e (i) NO production by NO synthase and (ii) CO production by heme oxyg enase. We analyze here the contributions of these two pathways to IL1, TNF, lipopolysaccharide and hemin treated brain capillary endothelial cells. Cytokines and LPS induced cGMP formation in manners that were completely prevented by LY 83,583, methylene blue and by cyclosporin A . They were partially inhibited by inhibitors of NO synthase. Cyclospo rin A acts by a posttranscriptional mechanism. Cells constitutively ex pressed mRNAs for heme oxygenase-1. Expression was enhanced by hemin b ut not by IL1 or lipopolysaccharide. Induction of heme oxygenase-1 and its inhibition by Sn protoporphyrin IX had no effect on cGMP levels. (C) 1995 Academic Press. Inc.