The effects of glucagon-like peptide-1 receptor agonists on sympathetic neuron activity

Hypertension Research https://doi.org/10.1038/s41440-026-02633-5 ARTICLE The effects of glucagon-like peptide-1 receptor agonists on sympathetic neuron activity Yui Koyanagi1 Kamon Iigaya1 Keiko Ikeda2 Hiroshi Onimaru1 Masahiko Izumizaki1 ● ● ● ● 1234567890();,: 1234567890();,: Received: 24 August 2025 / Revised: 15 March 2026 / Accepted: 26 March 2026 © The Author(s) 2026. This article is published with open access Abstract Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used to manage type 2 diabetes mellitus. However, there are reports indicating that patients administered GLP-1 receptor agonists often experience an increased heart rate. Although activation of the sympathetic nervous system may be involved in this response, the detailed mechanisms of action of GLP-1 receptor agonists are still not well understood. We hypothesized that GLP-1 receptor agonists could excite sympathetic nerve activity through direct effects on sympathetic-related neurons in the spinal cord and the medulla oblongata. Therefore, we examined the effects of a major GLP-1 receptor agonist, exendin-4, on sympathetic nerve activity at three different levels using in vitro preparations: (1) sympathetic nerve activity from the sympathetic nerve trunk, (2) preganglionic neurons in the intermediolateral cell column at the Th2–4 level of the spinal cord and (3) neurons in the rostral ventrolateral medulla corresponding to the C1 pressor area. Brainstem-spinal cord preparations were isolated from newborn rats (P0-P4) under deep isoflurane anesthesia and superfused with artificial cerebrospinal fluid, bubbled with 95% O2 and 5% CO2 at 25–26 °C. We found that 20–100 nM exendin-4 induced an increase in sympathetic nerve activity and the effect was blocked by the application of a GLP-1 antagonist. The application of 100 nM exendin-4 also induced membrane depolarization of the intermediolateral cell column and rostral ventrolateral medulla neurons. These results suggested that exendin-4 could induce increased sympathetic nerve activity via excitation of sympathetic-related neurons in the medulla and spinal cord. Keywords Glucagon-like peptide-1 Exendin-4 Sympathetic nerve activity Rostral ventrolateral medulla Drug-induced tachycardia ● ● Introduction Glucagon-like-peptide 1 (GLP-1) is a neuropeptide secreted by enteroendocrine L cells in the small intestine. It acts as an incretin and exerts a variety of physiological and pharmacological effects such as the promotion of insulin secretion [1]. GLP-1 is also produced by preproglucagon neurons in several brain regions including the nucleus Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41440026-02633-5. * Hiroshi Onimaru 1 Department of Physiology, Showa Medical University School of Medicine, Tokyo 142-8555, Japan 2 Deptartment of Oral Physiology, Showa Medical University School of Dentistry, Tokyo 142-8555, Japan ● ● tractus solitarius (NTS), and is involved in various brain functions such as the regulation of food intake and sympathetic nerve activity (SNA) [2–5]. The physiological properties of GLP-1 receptor agonists have led to their development as a class of medications that effectively reduce HbA1c levels and promote body weight loss, thereby offering a significant advantage in the comprehensive management of type 2 diabetes mellitus as reviewed by Rolek et al. [6]. or Masuda et al. [7]. GLP-1 receptor agonists are also recognized as novel drugs that reduce the incidence of cardiovascular events such as myocardial infarction, a common underlying cause of heart failure [8, 9]. Thus, it is a recent trend for diabetic patients with heart failure to receive GLP-1 receptor agonists [10]. However, there are reports that patients frequently experience an increase of heart rate after using GLP-1 receptor agonists [11]. Several previous studies have shown that GLP-1 receptor agonists cause tachycardia in animals [12, 13] and humans [14]. Moreover, Jorsal et al. [15] demonstrated that liraglutide, a GLP-1 receptor agonist, Y. Koyanagi et al. Graphical Abstract 3) RVLM 1) 2) Th2 IML st SNA increased serious adverse events such as ventricular tachycardia and atrial fibrillation in patients with stable chronic heart failure. Yamamoto et al. [12] reported that GLP-1 agonists dosedependently increased blood pressure and heart rate in rats probably via activation of neurons in autonomic control sites in the brain, including medullary catecholamine neurons that provide input to sympathetic preganglionic neurons. Holt et al. [2] showed that the application of GLP-1 receptor agonists increased blood pressure and heart rate, and suggested that GLP-1 agonists could increase cardiac sympathetic preganglionic neuron activity in mice. In contrast, Oshima et al. [16] showed that presympathetic neurons in the rostral ventrolateral medulla (RVLM) of newborn rats were hyperpolarized during the application of GLP-1 peptide. They suggested that GLP-1 could cause a decrease in blood pressure. Thus, the effects of GLP-1 agonists on SNA and the pathways of action remain to be clarified. In the present study, we aimed to reveal how GLP-1 receptor agonists could affect the sympathetic nervous system. For this purpose, we used in vitro preparations from newborn rats [16–18] and exendin-4 (also known as exenatide), a GLP-1 agonist that has been most commonly used in animal experiments. We investigated the effects of exendin-4 on (1) sympathetic nerve output, (2) preganglionic neurons (and interneurons) in the intermediate IML RVLM lateral cell column (IML) of the thoracic cord, and (3) neurons in the RVLM, including presympathetic neurons. Methods Preparations The experimental protocols were approved by the Institutional Animal Care and Use Committee of Showa University (approval no. 124046). Experiments were performed using brainstem-spinal cord preparations (or spinal cord block preparations) from newborn Wistar rats (age: 0–4 days, either sex). Rats were deeply anesthetized with isoflurane, and the brainstem and/ or spinal cord were isolated and placed in a 2 ml experimental chamber. The brainstem was rostrally cut at a level just rostral to the anterior inferior cerebellar artery. Preparations were superfused at a rate of 3.0 ml/min with the following artificial cerebrospinal fluid (ACSF) [19] (in mM): 124 NaCl, 5.0 KCl, 1.2 KH2PO4, 2.4 CaCl2, 1.3 MgCl2, 26 NaHCO3 and 30 glucose, equilibrated with 95% O2 and 5% CO2, pH 7.4, at 26–27 °C. To evaluate the effects of the drug on different levels of neuronal activity involved in sympathetic nerve outputs, we performed experiments using the following three types of in vitro preparations: The effects of glucagon-like peptide-1 receptor agonists on sympathetic neuron activity 1) Sympathetic nerve retained preparation: SNA was recorded in preparations with the thoracic sympathetic nerve trunk, as previously described [17]. Inspirator (...truncated)