TETRAHYDROBIOPTERIN AND GTP CYCLOHYDROLASE-I IN A RAT MODEL OF ENDOTOXIC-SHOCK - RELATION TO NITRIC-OXIDE SYNTHESIS

Induction of the inducible isoform of nitric oxide synthase (iNOS) in various types of cells is implicated as the cause of septic shock. We evaluated the concentration of tetrahydrobiopterin (BH4), a cofactor o f NOS, in plasma and various other tissues of rats treated with lipopo lysaccharide (LPS; 10 mg/kg I.v.). The activity of GTP cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in the de novo synthesis of BH4, in rat tissues was also determined. Three hours after adminis tration of LPS, rats showed plasma levels of BH4 and NOx (NO3- and NO2 -) that were elevated by 137 and 206 %, respectively. GTPCH was expres sed in liver and, to a lesser extent, in the lung, heart and kidney of control rats. In control rats, although a high concentration of BH4 w as detected in the liver, its level was lower in lung, heart, kidney a nd aorta. Three hours after LPS administration, a significant increase in BH4 concentration and/or GTPCH activity was observed in all tissue s examined except the liver. Our results demonstrate that the de novo synthesis of BH4 is upregulated by LPS in the rat in vivo, which may, at least in part, account for the increases in plasma level and tissue concentration of BH4 after the administration of LPS.