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(Hypertension. 1997;30:922-927.)
© 1997 American Heart Association, Inc.

Articles

Parathyroid Hormone–Related Protein Upregulates Interleukin-1ß–Induced Nitric Oxide Synthesis

Bingbing Jiang; Shigeto Morimoto; Jin Yang; Keisuke Fukuo; Atsushi Hirotani; Shoichi Kitano; ; Toshio Ogihara

From the Department of Geriatric Medicine, Osaka University Medical School, Japan.

Correspondence to Shigeto Morimoto, MD, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan.

Abstract The effect of parathyroid hormone–related protein on interleukin-1ß–induced nitric oxide production was studied in rat vascular smooth muscle cells. Interleukin-1ß time- and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyroid hormone–related protein(1-34) alone up to 10^-7 mol/L had no obvious effect, but significantly increased the cytokine-induced nitrite production. RNA analysis revealed that the synergistic effect of parathyroid 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, which is a cofactor of nitric oxide synthase. The increased nitric oxide release induced by interleukin-1ß or interleukin-1ß with parathyroid hormone–related protein(1-34) was completely inhibited by coincubation with 3x10^-3 mol/L N^G-monomethyl-l-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-1ß induction of nitric oxide, which might be mediated by endogenous parathyroid hormone–related protein. Neutralization of exogenous or endogenous parathyroid hormone–related protein with antibody attenuated the synergistic effect of parathyroid hormone–related protein, but did not affect interleukin-1ß induction of nitric oxide. These results suggest that locally produced parathyroid hormone–related protein acts as a synergistic regulator upregulating interleukin-1ß–induced nitric oxide synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in some pathological processes such as atherosclerosis and hypertension.

Key Words: parathyroid hormones • interleukin-1 • nitric oxide • RNA, messenger • muscle, smooth, vascular • rats

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