GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons.
OBJECTIVE
glucagon-like peptide 1 (GLP-1) is an incretin hormone released from the gut in response to food intake. Whereas GLP-1 acts in the periphery to inhibit glucagon secretion and stimulate insulin release, it also acts in the central nervous system to mediate autonomic control of feeding, body temperature, and cardiovascular function. Because of its role as an incretin hormone, GLP-1 receptor analogs are used as a treatment for type 2 diabetes. Central or peripheral administration of GLP-1 increases blood pressure and heart rate, possibly by activating brainstem autonomic nuclei and increasing vagus nerve activity. However, the mechanism(s) by which GLP-1 receptor stimulation affects cardiovascular function are unknown. We used the long-lasting GLP-1 receptor agonist Exendin-4 (Ex-4) to test the hypothesis that GLP-1 signalling modulates central parasympathetic control of heart rate.


RESULTS
using a telemetry system, we assessed heart rate in mice during central Ex-4 administration. Heart rate was increased by both acute and chronic central Ex-4 administration. Spectral analysis indicated that the high frequency and low frequency powers of heart rate variability were diminished by Ex-4 treatment. Finally, Ex-4 decreased both excitatory glutamatergic and inhibitory glycinergic neurotransmission to preganglionic parasympathetic cardiac vagal neurons.


CONCLUSIONS
these data suggest that central GLP-1 receptor stimulation diminishes parasympathetic modulation of the heart thereby increasing heart rate.
Griffioen
Kathleen J
KJ
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Wan
Ruiqian
R
Okun
Eitan
E
Wang
Xin
X
Lovett-Barr
Mary Rachael
MR
Li
Yazhou
Y
Mughal
Mohamed R
MR
Mendelowitz
David
D
Mattson
Mark P
MP
D000818:Animals; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide