Central Glucagon-like Peptide-1 Receptor Signaling via Brainstem Catecholamine Neurons Counteracts Hypertension in Spontaneously Hypertensive Rats

Kenichi Katsurada,Boyang Zhang,Yuko Maejima,Shyam S Nandi,Kaushik P Patel,Kazuomi Kario,Neeru M Sharma,Toshihiko Yada,Toshinobu Saito,Masanori Nakata

doi:10.1038/s41598-019-49364-x

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists, widely used to treat type 2 diabetes, reduce blood pressure (BP) in hypertensive patients. Whether this action involves central mechanisms is unknown. We here report that repeated lateral ventricular (LV) injection of GLP-1R agonist, liraglutide, once daily for 15 days counteracted the development of hypertension in spontaneously hypertensive rats (SHR). In parallel, it suppressed urinary norepinephrine excretion, and induced c-Fos expressions in the area postrema (AP) and nucleus tractus solitarius (NTS) of brainstem including the NTS neurons immunoreactive to dopamine beta-hydroxylase (DBH). Acute administration of liraglutide into fourth ventricle, the area with easy access to the AP and NTS, transiently decreased BP in SHR and this effect was attenuated after lesion of NTS DBH neurons with anti-DBH conjugated to saporin (anti-DBH-SAP). In anti-DBH-SAP injected SHR, the antihypertensive effect of repeated LV injection of liraglutide for 14 days was also attenuated. These findings demonstrate that the central GLP-1R signaling via NTS DBH neurons counteracts the development of hypertension in SHR, accompanied by attenuated sympathetic nerve activity.

Highlights

Www.nature.com/scientificreports can pass the blood brain barrier[19,20,21]
To gain further insight into the central neuron mediating the GLP-1 action, we focused on the nucleus tractus solitarius (NTS) catecholamine neurons expressing dopamine beta-hydroxylase (DBH), since DBH converts dopamine to norepinephrine and the NTS DBH neuron is implicated in regulation of cardiovascular functions
We have shown that repeated lateral ventricular (LV) injection of liraglutide once a day for 15 days counteracted the development of hypertension in spontaneously hypertensive rat (SHR), suppressed the norepinephrine excretion, and induced c-Fos expressions in NTS DBH neurons

Summary

Introduction

Www.nature.com/scientificreports can pass the blood brain barrier[19,20,21]. the mechanisms underlying the central action of GLP-1R agonists to lower BP remain to be fully elucidated. It is well known that development and progression of cardiovascular disease is strongly associated with sympathetic hyperactivity and treatment with sympathoinhibition probably leads to suppression of cardiovascular events[22,23] These strong and definite cardiovascular effects of liraglutide could be independent on the glucose lowering and associated effects. Based on these results form LEADER and SUSTAIN-6 trials we hypothesized that liraglutide exhibits antihypertensive effect accompanied with sympathoinhibition leading to suppression of cardiovascular events. To test this hypothesis we assessed the central action of liraglutide and underlying mechanism to counteract hypertension in spontaneously hypertensive rat (SHR) that has hypertensive and sympathoexcitative properties. The lesion of NTS DBH neurons by anti-DBH-SAP attenuated both acute depressor effect of 4V injection of liraglutide and chronic antihypertensive effect of LV injection of liraglutide

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Conclusion