Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

Abstract

Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

“…It was also verified that the presence of the non-obstructing vascular catheter in the renal vein did not affect GFR or RPF in the left kidney, because there was no difference between the two kidneys in these respects. Moreover, although there is evidence that GLP-1 may increase GFR [29], and raise blood pressure and heart rate in rats [30], when administered in very high concentrations that result in plasma concentrations clearly exceeding physiological levels as in the present study, these parameters (blood pressure, heart rate, GFR, and RPF) remained stable and were not altered by the peptide infusions. It is, therefore, reasonable to speculate that several mechanisms may be involved in the renal handling of peptide hormones, and this explains the differential degree of extraction that occurs for GLP-1 and exendin-4.…”

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

“…By contrast, decerebrate rats lacking all neural communication between the caudal brainstem and hypothalamus (histologically confirmed complete transections) showed the same suppression of intake and gastric emptying rate for peripheral GLP-1R agonists as that observed in neurologically intact control rats. These results thereby show that neuronal activation of paraventricular nucleus, arcuate nucleus or other hypothalamic/forebrain neurons by peripheral GLP-1R treatment observed in intact rats 10,11,18,42 is not required for suppression of intake and gastric emptying rate as is clear from the decerebrate data.…”

“…9,10 Endogenous release or intraperitoneal GLP-1R agonist delivery triggers a set of responses that include reduced food intake, [11][12][13][14] inhibition of gastric emptying, 9,14 stimulation of glucosedependent insulin secretion 15,16 and tachycardia. [17][18][19][20][21] GLP-1R ligand is also supplied by proglucagon-expressing neurons of the caudal brainstem that project to GLP-1Rs, which are distributed throughout the brain. [22][23][24] It is interesting to note that stimulation of central GLP-1R results in many of the same responses, for example, inhibition of food intake and increased insulin secretion, as are observed following peripheral ligand injection.…”

“…The vagally transmitted effects of peripheral GLP-1R stimulation therefore involve behavioral and autonomic effector pathways that are downstream of CNS processing. [17][18][19]21,25 Structures in the ascending visceral afferent pathway, which includes nuclei of the caudal brainstem (NTS; parabrachial nucleus), hypothalamus (lateral hypothalamus; paraventricular nucleus) and basal forebrain (bed nucleus of stria terminalis; central nucleus of the amygdala), 26,27 may therefore play a role in mediating responses triggered by peripheral GLP-1R agonist treatmentA role. Similarly for the central GLP-1 system, direct central GLP-1R ligand administration activates neurons in many of the same central structures that show GLP-1-binding 23 and/or express GLP-1R mRNA.…”

“…33 Hypothalamic processing had been hypothesized to mediate the profile of responses evoked by peripheral GLP-1R ligand delivery. 11,30,42 Peripheral administration of GLP-1R agonists induces central neuronal activation, as indicated by Fos-like immunoreactivity 10,11,18,42 and a magnetic resonance imaging signal, 30 in the paraventricular nucleus and, in some reports, the arcuate nucleus and ventral medial hypothalamus nuclei. The neural mediation of the intake inhibition resulting from peripheral GLP-1R stimulation was examined earlier 11 by interrupting connections between the caudal brainstem and hypothalamus with midbrain knife-cuts.…”