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% O 2 and 5% CO 2 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.
Koyanagi et al. (Fri,) studied this question.