title: Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model.
abstract: Serelaxin, recombinant human relaxin-2, modulates endothelial vasodilatory functionality and is under evaluation for treatment of acute heart failure. Little is known about acute effects on cerebral perfusion. We tested the hypothesis that Serelaxin might also have effects on the cerebral microcirculation in a sheep model, which resembles human brain structure quite well. We used laser Doppler flowmetry and sidestream dark-field (SDF) imaging techniques, which are reliable tools to continuously assess dynamic changes in cerebral perfusion. Laser Doppler flowmetry shows that bolus injection of 30 μg Serelaxin/kg body wt induces an increase (P = 0.006) to roughly 150% of cortical cerebral blood flow (CBF), whereas subcortical CBF remains unchanged (P = 0.688). The effects on area-dependent CBF were significantly different after the bolus injection (P = 0.042). Effects on cortical CBF were further confirmed by SDF imaging. The bolus injection of Serelaxin increased total vessel density to 127% (P = 0.00046), perfused vessel density to 145% (P = 0.024), and perfused capillary density to 153% (P = 0.024). Western blotting confirmed the expression of relaxin receptors RXFP1 and truncated RXFP2-variants in the respective brain regions, suggesting a possible contribution of RXFP1 on the effects of Serelaxin. In conclusion, the injection of a high dose of Serelaxin exerts quick effects on the cerebral microcirculation. Therefore, Serelaxin might be suitable to improve cortical microcirculation and exert neuroprotective effects in clinically relevant scenarios that involve cortical hypoperfusion. These findings need to be confirmed in relevant experimental settings involving cerebral cortical hypoperfusion and can possibly be translated into clinical practice.
authors.affiliation: Institute for Laboratory Animal Science and Welfare, Jena University Hospital, Friedrich Schiller University, Jena, Germany;
authors.forename: Sabine J
authors.initials: SJ
authors.lastname: Bischoff
authors.affiliation: Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, Jena, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Institute of Medical Statistics, Computer Sciences and Documentation Science, Jena University Hospital, Friedrich Schiller University, Jena, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehmann
authors.affiliation: Department of Otorhinolaryngology, Jena University Hospital, Friedrich Schiller University, Jena, Germany;
authors.forename: Andrey
authors.initials: A
authors.lastname: Irintchev
authors.affiliation: Institute for Laboratory Animal Science and Welfare, Jena University Hospital, Friedrich Schiller University, Jena, Germany;
authors.forename: Harald
authors.initials: H
authors.lastname: Schubert
authors.affiliation: Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Jung
authors.affiliation: Department of Neurology, Jena University Hospital, Friedrich Schiller University, Jena, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Institute for Biochemistry II, Jena University Hospital, Friedrich Schiller University, Jena, Germany;
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.affiliation: Orthopaedic Department, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Matziolis
authors.affiliation: Department of Neurology, Jena University Hospital, Friedrich Schiller University, Jena, Germany; and Orthopaedic Department, Jena University Hospital, Friedrich Schiller University, Jena, Germany rene.schiffner@med.uni-jena.de.
authors.forename: René
authors.identifier: 0000-0001-9546-6273
authors.initials: R
authors.lastname: Schiffner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005260:Female; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D008833:Microcirculation / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012065:Relaxin / Q000494:pharmacology*; D012756:Sheep; D034561:Sheep, Domestic
chemical_list: D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D011994:Recombinant Proteins; C033395:relaxin receptors; D012065:Relaxin
keywords: Serelaxin; cerebral blood flow; relaxin receptors; relaxin-2; sheep model