title: Acute intravenous injection of serelaxin (recombinant human relaxin-2) causes rapid and sustained bradykinin-mediated vasorelaxation.
abstract: BACKGROUND
  A recent clinical trial (RELAXin in Acute Heart Failure [RELAX-AHF]) demonstrated that 48 hours of continuous intravenous infusion of the vasorelaxant peptide serelaxin (recombinant human relaxin-2) to patients with acute heart failure reduced cardiovascular mortality at 180 days. The persistence of a vasorelaxant response as a potential mechanism for this long-term benefit and the vascular effects of a bolus intravenous injection of serelaxin have not been examined. This study investigates changes in resistance artery reactivity and passive mechanical wall properties following an intravenous serelaxin injection and whether these vascular effects persist in the absence of detectable circulating serelaxin.
  
  
  RESULTS
  Male rats were injected with 13.3 μg/kg serelaxin into the tail vein; mesenteric arteries were assessed 3 and 24 hours after treatment by using wire-myography. Serelaxin increased basal nitric oxide synthase activity and reduced maximal contraction to endothelin-1 at 3 hours after administration. Serelaxin treatment also selectively enhanced bradykinin-mediated endothelium-dependent relaxation. This effect was sustained for 24 hours in the absence of circulating serelaxin. Serelaxin-mediated augmentation of bradykinin-evoked relaxation involved endothelium-derived hyperpolarization after 3 hours and prostacyclin-mediated relaxation after 24 hours. Furthermore, upregulation of inducible nitric oxide synthase, phosphorylation of protein kinase B at Ser473 and endothelial nitric oxide synthase at Ser1177 was observed at 24 hours after serelaxin injection. There were no effects of serelaxin on passive arterial wall stiffness.
  
  
  CONCLUSIONS
  Our data show that a bolus intravenous injection of serelaxin modulates endothelial vasodilator function 3 hours after administration, an effect that was sustained for 24 hours. The prolonged bradykinin-mediated vasorelaxation is principally mediated through prostacyclin.
authors.affiliation: Department of Zoology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Chen Huei
authors.initials: CH
authors.lastname: Leo
authors.forename: Maria
authors.initials: M
authors.lastname: Jelinic
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Parry
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D012065:Relaxin / Q000008:administration & dosage*; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D011994:Recombinant Proteins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C577649:serelaxin protein, human; D009569:Nitric Oxide; D012694:Serine; D012065:Relaxin; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D001920:Bradykinin
keywords: endothelium; endothelium‐derived hyperpolarization; nitric oxide; prostacyclin; serelaxin