Increased inducible nitric oxide synthase protein but limited nitric oxide formation occurs in astrocytes of the hph-1 (tetrahydrobiopterin deficient) mouse

It has been suggested that decreased tetrahydrobiopterin (BH(4)) availability may be a useful tool for limiting excessive nitric oxide (NO) formation. In order to test this hypothesis we utilised cultured astrocytes derived from the brain of the hph-1 (BH(4) deficient) mouse. In response to treatment with Lipopolysaccharide and interferon-gamma (LPS/gamma IFN) levels of BH(4) doubled in both wild type and hph-1 astrocytes. However, levels of BH(4) in hph-1 astrocytes remained only 25% of the wild type astrocytes. Nitric oxide formation, measured with an NO-electrode, was 45% less from LPS/gamma IFN stimulated hph-1 astrocytes compared with wild type stimulated astrocytes. Ln contrast, iNOS specific activity and iNOS protein were enhanced in hph-1 stimulated astrocytes by 40 and 60%, respectively when compared with wild type. In conclusion it appears that whilst a decrease in BH(4) may limit NO release per se, the possibility and consequences of long term 'over' induction of iNOS protein requires further consideration. (C) 1998 Elsevier Science B.V. All rights reserved.