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- Title
GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure.
- Authors
Kim, Minsuk; Platt, Mathew J; Shibasaki, Tadao; Quaggin, Susan E; Backx, Peter H; Seino, Susumu; Simpson, Jeremy A; Drucker, Daniel J
- Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists exert antihypertensive actions through incompletely understood mechanisms. Here we demonstrate that cardiac Glp1r expression is localized to cardiac atria and that GLP-1R activation promotes the secretion of atrial natriuretic peptide (ANP) and a reduction of blood pressure. Consistent with an indirect ANP-dependent mechanism for the antihypertensive effects of GLP-1R activation, the GLP-1R agonist liraglutide did not directly increase the amount of cyclic GMP (cGMP) or relax preconstricted aortic rings; however, conditioned medium from liraglutide-treated hearts relaxed aortic rings in an endothelium-independent, GLP-1R-dependent manner. Liraglutide did not induce ANP secretion, vasorelaxation or lower blood pressure in Glp1r?/? or Nppa?/? mice. Cardiomyocyte GLP-1R activation promoted the translocation of the Rap guanine nucleotide exchange factor Epac2 (also known as Rapgef4) to the membrane, whereas Epac2 deficiency eliminated GLP-1R-dependent stimulation of ANP secretion. Plasma ANP concentrations were increased after refeeding in wild-type but not Glp1r?/? mice, and liraglutide increased urine sodium excretion in wild-type but not Nppa?/? mice. These findings define a gut-heart GLP-1R-dependent and ANP-dependent axis that regulates blood pressure.
- Subjects
GLUCAGON-like peptide-1 receptor; ANTIHYPERTENSIVE agents; CARDIAC glycosides; ATRIAL natriuretic peptides; BLOOD pressure measurement; HEART cells
- Publication
Nature Medicine, 2013, Vol 19, Issue 5, p567
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3128