Nitric oxide as a second messenger in parathyroid hormone-related protein signaling

L. Kalinowski, L. W. Dobrucki, T. Malinski

Research output: Contribution to journalArticlepeer-review

Abstract

Parathyroid hormone (PTH)-related protein (PTHrP) is produced in smooth muscles and endothelial cells and is believed to participate in the local regulation of vascular tone. No direct evidence for the activation of endothelium-derived nitric oxide (NO) signaling pathway by PTHrP has been found despite attempts to identify it. Based on direct in situ measurements, it is reported here for the first time that the human PTH/PTHrP receptor analogs, hPTH(1-34) and hPTHrP(1-34), stimulate NO release from a single endothelial cell. A highly sensitive porphyrinic microsensor with a response time of 0.1 ms and a detection limit of 1 nmol/l was used for the measurement of NO. Both hPTH(1-34) and hPTHrP(1-34) stimulated NO release at nanomolar concentrations. The peak concentration of 0.1 μmol/l hPTH(1-34)- and 0.1 μmol/l hPTHrP(1-34)-stimulated NO release was 175 ± 9 and 248 ± 13 nmol/l respectively. This represents about 30%-40% of maximum NO concentration recorded in the presence of (0.1 μmol/l) calcium ionophore. Two competitive PTH/PTHrP receptor antagonists, 10 μmol/l [Leu11,D-Trp12]-hPTHrP(7-34)amide and 10 μmol/l [Nle8,18,Tyr34]-bPTH(3-34)amide, were equipotent in antagonizing hPTH(1-34)-stimulated NO release; [Leu11,D-Trp12]-hPTHrP(7-34)amide was more potent than [Nle8,18,Tyr34]-bPTH(3-34)amide in inhibiting hPTHrP(1-34)-stimulated NO release. The PKC inhibitor, H-7 (50 μmol/l), did not change hPTH(1-34)- and hPTHrP(1-34)-stimulated NO release, whereas the combined effect of 10 μmol/l of the cAMP antagonist, Rp-cAMPS, and 50 μmol/l of the calmodulin inhibitor, W-7, was additive. The present studies show that both hPTH(1-34) and hPTHrP(1-34) activate NO production in endothelial cells. The activation of NO release is through PTH/PTHrP receptors and is mediated via the calcium/calmodulin pathway.

Original languageEnglish (US)
Pages (from-to)433-440
Number of pages8
JournalJournal of Endocrinology
Volume170
Issue number2
DOIs
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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