PARATHYROID HORMONE-RELATED PROTEIN UP-REGULATES INTERLEUKIN-1-BETA-INDUCED NITRIC-OXIDE SYNTHESIS

The effect of parathyroid hormone-related protein on interleukin-1 bet a-induced nitric oxide production was studied in rat vascular smooth m uscle cells. Interleukin-1 beta time-and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyro id hormone-related protein(1-34) alone up to 10(-7) mol/L had no obvio us effect, but significantly increased the cytokine-induced nitrite pr oduction. RNA analysis revealed that the synergistic effect of parathy roid hormone-related protein(1-34) resulted from a potentiation of the expression of inducible nitric oxide synthase and GTP-cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, w hich is a cofactor of nitric oxide synthase. The increased nitric oxid e release induced by interleukin-1 beta or interleukin-1 beta with par athyroid hormone-related protein(1-34) was completely inhibited by coi ncubation with 3x10(-3) mol/L N-G-monomethyl-1-arginine, a competitive inhibitor of nitric oxide synthase, or with 10(-3) mol/L 2,4-diamino- 6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I. Endothelin- 1 potentiated interleukin-1 beta induction of nitric oxide, which migh t be mediated by endogenous parathyroid hormone-related protein. Neutr alization of exogenous or endogenous parathyroid hormone-related prote in with antibody attenuated the synergistic effect of parathyroid horm one-related protein, but did not affect interleukin-1 beta induction o f nitric oxide. These results suggest that locally produced parathyroi d hormone-related protein acts as a synergistic regulator upregulating interleukin-1 beta-induced nitric oxide synthesis in the cardiovascul ar system, and thereby may affect vascular tone and/or vascular remode ling after vascular injury in some pathological processes such as athe rosclerosis and hypertension.