title: GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure.
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.
authors.affiliation: Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Minsuk
authors.initials: M
authors.lastname: Kim
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Platt
authors.forename: Tadao
authors.initials: T
authors.lastname: Shibasaki
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001794:Blood Pressure; D006152:Cyclic GMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020098:Natriuretic Peptide, C-Type / Q000235:genetics; D010477:Perfusion; D011498:Protein Precursors / Q000235:genetics; D018027:Receptors, Glucagon / Q000378:metabolism*; D014664:Vasodilation
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D020662:Guanine Nucleotide Exchange Factors; C431578:Nppa protein, mouse; D011498:Protein Precursors; C486707:Rapgef4 protein, mouse; D018027:Receptors, Glucagon; D020098:Natriuretic Peptide, C-Type; D000069450:Liraglutide; D009320:Atrial Natriuretic Factor; D052216:Glucagon-Like Peptide 1; D006152:Cyclic GMP
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