Parathyroid hormone-related protein inhibits indothelin-1 production.
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 Ng-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 5x10(-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.
Jiang
B
B
Department of Geriatric Medicine, University Medical School, Osaka, Japan.
Morimoto
S
S
Fukuo
K
K
Hirotani
A
A
Tamatani
M
M
Nakahashi
T
T
Nishibe
A
A
Niinobu
T
T
Hata
S
S
Chen
S
S
Ogihara
T
T
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000378:metabolism*
D016232:Endothelins; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins