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

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.