Central hypotensive effects of neuropeptide y are modulated by endothelial nitric oxide synthase after activation by ribosomal protein S6 kinase

Pei Wen Cheng, Alexander T H Wu, Pei Jung Lu, Ya Chun Yang, Wen Yu Ho, Hui Ching Lin, Michael Hsiao, Ching Jiunn Tseng

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background and purpose: Neuropeptide Y (NPY) is a 36-amino acid polypeptide found abundantly in the central and peripheral nervous systems. NPY exerts a potent depressor effect via the activation of both Y1 and Y 2 receptors in the nucleus tractus solitarii (NTS) of rats. However, the precise mechanisms involved in this NPY-mediated action remained unclear. Experimental approach: Effects of a selective antagonist of Y1 receptors, a PKC inhibitor, a PI3 kinase inhibitor, a NOS inhibitor, an endothelial NOS (eNOS)-selective inhibitor, a neuronal NOS (nNOS)-specific inhibitor or a MAPK inhibitor, on responses to microinjection of NPY into the NTS of Wistar-Kyoto rats were studied to determine the underlying mechanisms. Blood pressure and heart rate were measured and, in NTS, protein phosphorylation assessed by immunohistochemical techniques. Key results: Unilateral microinjection of exogenous NPY (4.65 pmol/60 nL) into the NTS of urethane-anesthetized Wistar-Kyoto rats markedly decreased blood pressure and heart rate. Microinjection of the Y1 receptor antagonist BIBP3226 or the Gi/Go-protein inhibitor, Pertussis toxin, into the NTS attenuated these NPY-induced hypotensive effects. A selective Y1 receptor agonist increased expression of ERK1/2, ribosomal protein S6 kinase (RSK) and the phosphorylation of eNOS. RSK also bound directly to eNOS and induced its phosphorylation at Ser1177. Pretreatment of the NTS with an eNOS inhibitor, but not a nNOS inhibitor, attenuated the NPY-induced hypotensive effects. Conclusions and implications: Together, these results suggested that NPY-induced depressor effects were mediated by activating NPY Y1 receptor-PKC-ERK-RSK-eNOS and Ca2+-eNOS signalling pathways, which are involved in regulation of blood pressure in the NTS.

Original languageEnglish
Pages (from-to)1148-1160
Number of pages13
JournalBritish Journal of Pharmacology
Volume167
Issue number5
DOIs
Publication statusPublished - Nov 2012

Keywords

  • extracellular signal-regulated kinases1/2
  • neuropeptide Y
  • nitric oxide
  • nucleus tractus solitarii
  • ribosomal protein S6 kinase

ASJC Scopus subject areas

  • Pharmacology

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