Parathyroid Hormone–Related Protein Inhibits Endothelin-1 Production

Abstract

Abstract The effect of human parathyroid hormone–related protein, a powerful vasodilator, on endothelin-1 production in cultured bovine pulmonary arterial endothelial cells was studied. Treatment with parathyroid hormone–related protein(1-34) at concentrations of 10 ⁻⁹ to 10 ⁻⁶ mol/L for 24 hours caused dose-dependent suppression of the secretion of endothelin-1, with maximal suppression at 10 ⁻⁷ mol/L to 74% of the control value. This inhibitory effect was completely abolished by coincubation 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 suppressive effect of parathyroid hormone–related protein(1-34) on endothelin-1 secretion, and further addition of 5×10 ⁻³ mol/L l -arginine significantly 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. Northern blot analysis revealed that parathyroid hormone–related protein(1-34) inhibited both basal and thrombin-induced endothelin-1 gene expression. These findings suggest that the vasodilating property of parathyroid hormone–related protein may be mediated in part through its inhibitory effect on endothelin-1 production, which is probably mediated through nitric oxide and cGMP in endothelial cells. Thus, a feedback regulatory mechanism may exist between parathyroid hormone–related protein and endothelin-1 in the vascular wall.