Problems with GLP-1r agonist.
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J Clin Invest, July 2002, Volume 110, Number 1, 43-52
Copyright ©2002 by the American Society for Clinical Investigation
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Article
Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons
Hiroshi Yamamoto1, Charlotte E. Lee1, Jacob N. Marcus1, Todd D. Williams2, J. Michael Overton2, Marisol E. Lopez1, Anthony N. Hollenberg1, Laurie Baggio3, Clifford B. Saper4, Daniel J. Drucker3 and Joel K. Elmquist1,4
1 Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA 2 Department of Nutrition, Food, and Exercise Science, Program in Neuroscience, Florida State University, Tallahassee, Florida, USA 3 Department of Medicine, Toronto General Hospital, and the Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada 4 Department of Neurology, Beth Israel Deaconess Medical Center, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: Joel K. Elmquist, Division of Endocrinology, Beth Israel Deaconess Medical Center, 347 Research North, 99 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-3218; Fax: (617) 667-2927; E-mail: jelmquis@caregroup.harvard.edu.
Received for publication April 3, 2002, and accepted in revised form May 28, 2002.
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. |
