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

• Published in: British journal of pharmacology Vol. 167; no. 5; pp. 1148 - 1160
• Main Authors: Cheng, Pei‐Wen, Wu, Alexander TH, Lu, Pei‐Jung, Yang, Ya‐Chun, Ho, Wen‐Yu, Lin, Hui‐Ching, Hsiao, Michael, Tseng, Ching‐Jiunn
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2012; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Blood pressure; Blood Pressure - physiology; Calcium - physiology; Extracellular Signal-Regulated MAP Kinases - physiology; extracellular signal‐regulated kinases1/2; Heart rate; Heart Rate - physiology; Hypotension - physiopathology; Kinases; Male; Medical sciences; neuropeptide Y; Neuropeptide Y - physiology; Neuropeptides; Nitric oxide; Nitric Oxide - physiology; Nitric Oxide Synthase Type III - physiology; nucleus tractus solitarii; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase C - physiology; Proteins; Rats; Rats, Inbred WKY; Receptors, Neuropeptide Y - physiology; Research Papers; ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases - physiology; Rodents; Solitary Nucleus - physiology; Neuropeptide Y; Enzyme; nucleus tractus solitarii; Transferases; Non-specific serine/threonine protein kinase; Peptide hormone; Central nervous system; Cardiovascular disease; extracellular signal-regulated kinasesl/2; Extracellular; Nitric-oxide synthase; Encephalon; Endothelium; Solitary nucleus; Hypotensive drug; Arterial hypotension; Nitric oxide; ribosomal protein S6 kinase; Oxidoreductases
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.02077.x

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 Y2 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.