title: Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure.
abstract: BACKGROUND
  To assess cardiovascular actions of APJ agonism during prolonged (Pyr(1))apelin-13 infusion and renin-angiotensin system activation.
  
  
  RESULTS
  Forty-eight volunteers and 12 patients with chronic stable heart failure attended a series of randomized placebo-controlled studies. Forearm blood flow, cardiac index, left ventricular dimensions, and mean arterial pressure were measured using bilateral venous occlusion plethysmography, bioimpedance cardiography, transthoracic echocardiography, and sphygmomanometry, respectively, during brief local (0.3-3.0 nmol/min) and systemic (30-300 nmol/min) or prolonged systemic (30 nmol/min) (Pyr(1))apelin-13 infusions in the presence or absence of renin-angiotensin system activation with sodium depletion or angiotensin II coinfusion. During sodium depletion and angiotensin II coinfusion, (Pyr(1))apelin-13-induced vasodilatation was preserved (P<0.02 for both). Systemic intravenous (Pyr(1))apelin-13 infusion increased cardiac index, whereas reducing mean arterial pressure and peripheral vascular resistance index (P<0.001 for all) irrespective of sodium depletion or angiotensin II (0.5 ng/kg per minute) coinfusion (P>0.05 for all). Prolonged 6-hour (Pyr(1))apelin-13 infusion caused a sustained increase in cardiac index with increased left ventricular ejection fraction in patients with chronic heart failure (ANOVA; P<0.001 for all).
  
  
  CONCLUSIONS
  APJ agonism has sustained cardiovascular effects that are preserved in the presence of renin-angiotensin system activation or heart failure. APJ agonism may hold major promise to complement current optimal medical therapy in patients with chronic heart failure.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00901719, NCT00901888, NCT01049646, NCT01179061.
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. gareth.barnes@ed.ac.uk
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Barnes
authors.forename: Shirjel
authors.initials: S
authors.lastname: Alam
authors.forename: Gordon
authors.initials: G
authors.lastname: Carter
authors.forename: Christian M
authors.initials: CM
authors.lastname: Pedersen
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Lee
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hubbard
authors.forename: Scott
authors.initials: S
authors.lastname: Veitch
authors.forename: Herim
authors.initials: H
authors.lastname: Jeong
authors.forename: Audrey
authors.initials: A
authors.lastname: White
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Cruden
authors.forename: Les
authors.initials: L
authors.lastname: Huson
authors.forename: Alan G
authors.initials: AG
authors.lastname: Japp
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000368:Aged; D000804:Angiotensin II / Q000008:administration & dosage; D000075244:Apelin Receptors; D001794:Blood Pressure / Q000187:drug effects; D002307:Cardiography, Impedance; D002319:Cardiovascular System / Q000187:drug effects*; D018592:Cross-Over Studies; D005260:Female; D005542:Forearm / Q000098:blood supply; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010991:Plethysmography; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D012084:Renin-Angiotensin System / Q000502:physiology*; D012964:Sodium / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide; D000804:Angiotensin II; D012964:Sodium
keywords: APJ; apelin; heart failure; human; vasodilatation