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

Abstract

BACKGROUND AND PURPOSENeuropeptide 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 APPROACHEffects 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 RESULTSUnilateral 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 Ser 1177 . Pretreatment of the NTS with an eNOS inhibitor, but not a nNOS inhibitor, attenuated the NPY-induced hypotensive effects. CONCLUSIONS AND IMPLICATIONSTogether, these results suggested that NPY-induced depressor effects were mediated by activating NPY Y1 receptor-PKC-ERK-RSK-eNOS and Ca 2+ -eNOS signalling pathways, which are involved in regulation of blood pressure in the NTS.

Inhibition of Mir-128-3p by Tongxinluo Protects Human Cardiomyocytes From Ischemia/Reperfusion Injury via Upregulation of P70s6k1/P-P70s6k1

“…This finding, to some extent, was consistent with our previous observations that TXL decreased myocardial infarct size induced by I/R through the protein kinase A (PKA)/eNOS pathway (Cheng et al, 2009;Li et al, 2010;Li X. D. et al, 2013). It was demonstrated that p70s6k activation by neuropeptide Y or cysteine-rich, angiogenic inducer 61, promoted eNOS phosphorylation in endothelial cells and led to blood vessel relaxation (Cheng et al, 2012;Hwang et al, 2015). Moreover, two other studies showed that increased p70s6k1 phosphorylation facilitated PKA expression and enhanced its activity in tissues (Soulard et al, 2010;Jiang et al, 2016).…”

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

“…NPY can regulate blood pressure, and the activation of adrenaline, by coupling to the NPY Y1 receptor. In transgenic rodents, over-expression of the NPY gene attenuated the elevation of blood pressure after central Nitric Oxide Synthase (NOS) inhibition administration; the injection of a selective Y1 receptor antagonist, BIBP3226, was shown to reverse this phenomenon centrally [131]. In mice, the specific deletion of the gene encoding NPY Y1 receptor results in changes in adrenergic activity, as well as enhanced biosynthesis and secretion of catecholamine [132].…”

“…In mice, the specific deletion of the gene encoding NPY Y1 receptor results in changes in adrenergic activity, as well as enhanced biosynthesis and secretion of catecholamine [132]. Peripherally, NPY activates the NPY Y1 receptor receptor and modulates vasoconstrictor or vasopressor responses [133], while centrally, these effects may be the total opposite, and are usually anti-hypertensive [131]. …”

“…A microinjection of NPY into the nucleus of the solitary tract can induce a dose-dependent reduction in both blood pressure and heart rate, while the NOS inhibitor, via NPY receptor-mediated downstream signaling, can cause the enhancement of systemic arterial pressure and renal sympathetic nerve activity [139]. In the nucleus of the solitary tract, NPY regulates blood pressure and exerts a depressor effect by activating two signaling pathways: the Y1 receptor-PKC-ERK-ribosomal protein S6 kinase (RSK)-eNOS pathway and the Ca 2+ -eN 1 S signaling system [131]. …”

Sustained cutaneous vasoconstriction during and following cyrotherapy treatment: Role of oxidative stress and Rho kinase

“…NPY concentration is increased by 300% following 10 min of cold exposure and remains elevated following removal of the stimulus (20, 34). Additionally, NPY increases Rho-kinase activity (7) which could contribute to the present findings.…”