PARATHYROID HORMONE-RELATED PROTEIN INHIBITS ENDOTHELIN-1 PRODUCTION

The effect of human parathyroid hormone-related protein, a powerful va sodilator, on endothelin-1 production in cultured bovine pulmonary art erial endothelial cells was studied. Treatment with parathyroid hormon e-related protein(1-34) at concentrations of 10(-9) to 10(-6) mol/L fo r 24 hours caused dose-dependent suppression of the secretion of endot helin-1, with maximal suppression at 10(-7) mol/L to 74% of the contro l value. This inhibitory effect was completely abolished by coincubati on with 100 ng/mL pertussis toxin, an inhibitor of GTP binding protein . Furthermore, addition of N-G-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, at 10(-3) mol/L significantly blocked the suppr essive effect of parathyroid hormone-related protein(1-34) on endothel in-1 secretion, and further addition of 5x10(-3) mol/L L-arginine sign ificantly attenuated the blocking effect of N-G-monomethyl-L-arginine. Parathyroid hormone-related protein(1-34) at 10(-7) mol/L resulted in an approximately fivefold increase in intracellular cGMP level. North ern blot analysis revealed that parathyroid hormone-related protein(1- 34) inhibited both basal and thrombin-induced endothelin-1 gene expres sion. These findings suggest that the vasodilating property of parathy roid hormone-related protein may be mediated in part through its inhib itory effect on endothelin-1 production, which is probably mediated th rough nitric oxide and cGMP in endothelial cells. Thus, a feedback reg ulatory mechanism may exist between parathyroid hormone-related protei n and endothelin-1 in the vascular wall.