title: Time-dependent activation of prostacyclin and nitric oxide pathways during continuous i.v. infusion of serelaxin (recombinant human H2 relaxin).
abstract: OBJECTIVE
  In the RELAX-AHF trial, a 48 h i.v. serelaxin infusion reduced systemic vascular resistance in patients with acute heart failure. Consistent with preclinical studies, serelaxin augments endothelial vasodilator function in rat mesenteric arteries. Little is known about the contribution of endothelium-derived relaxing factors after a longer duration of continuous serelaxin treatment. Here we have assessed vascular reactivity and mechanistic pathways in mesenteric arteries and veins and the aorta after 48 or 72 h continuous i.v. infusion of serelaxin.
  
  
  METHODS
  Male rats were infused with either placebo or serelaxin (13.3 μg·kg(-1) ·h(-1) ) via the jugular vein using osmotic minipumps. Vascular function was assessed using wire myography. Changes in gene and protein expression and 6-keto PGF1α levels were determined by quantitative PCR, Western blot and ELISA respectively.
  
  
  RESULTS
  Continuous i.v. serelaxin infusion augmented endothelium-dependent relaxation in arteries (mesenteric and aorta) but not in mesenteric veins. In mesenteric arteries, 48 h i.v. serelaxin infusion increased basal NOS activity, associated with increased endothelial NOS (eNOS) expression. Interestingly, phosphorylated-eNOS(Ser1177) , eNOS and basal NOS activity were reduced in mesenteric arteries following 72 h serelaxin treatment. At 72 h, serelaxin treatment improved bradykinin-mediated relaxation through COX2-derived PGI2 production.
  
  
  CONCLUSIONS
  Continuous i.v. serelaxin infusion enhanced endothelial vasodilator function in arteries but not in veins. The underlying mediator at 48 h was NO but there was a transition to PGI2 by 72 h. Activation of the PGI2 -dependent pathway is key to the prolonged vascular response to serelaxin treatment.
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Vic, Australia.
authors.forename: C H
authors.initials: CH
authors.lastname: Leo
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Vic, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Jelinic
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Vic, Australia.
authors.forename: H H
authors.initials: HH
authors.lastname: Ng
authors.affiliation: Department of Physiology and School of Rural Health, Monash University, Parkville, Vic, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Tare
authors.affiliation: School of BioSciences, The University of Melbourne, Parkville, Vic, Australia.
authors.forename: L J
authors.initials: LJ
authors.lastname: Parry
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology*; D007262:Infusions, Intravenous; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D008642:Mesenteric Veins / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology; D012065:Relaxin / Q000097:blood / Q000494:pharmacology*; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects
chemical_list: D011994:Recombinant Proteins; C577649:serelaxin protein, human; D009569:Nitric Oxide; D012065:Relaxin; D011464:Epoprostenol