title: Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis.
abstract: Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.
authors.affiliation: Investigational Intensive Care Unit, Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA. Sebastian.Rehberg@ukmuenster.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rehberg
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Linda
authors.initials: L
authors.lastname: Sousse
authors.forename: Eva
authors.initials: E
authors.lastname: Bartha
authors.forename: Collette
authors.initials: C
authors.lastname: Jonkam
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Hasselbach
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Martin
authors.initials: M
authors.lastname: Westphal
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D055624:Methicillin-Resistant Staphylococcus aureus / Q000472:pathogenicity; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000097:blood; D011023:Pneumonia, Staphylococcal / Q000150:complications / Q000382:microbiology; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000503:physiopathology; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000150:complications; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014668:Vasotocin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D042702:Angiopoietin-2; D017483:Receptors, Vasopressin; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; C082353:vasotocin, Phe(2)-Orn(8)-; D001127:Arginine Vasopressin; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D014668:Vasotocin