Blockage of arginine vasopressin receptor 2 prevents vascular leakage and reduces increase in pulmonary vascular resistance in ovine sepsis

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Blockage of arginine vasopressin receptor 2 prevents vascular leakage and reduces increase in pulmonary vascular resistance in ovine sepsis Ernesto Lopez, Osamu Fujiwara, Baigalmaa Enkhtaivan, Satoshi Fukuda, Koji Ihara, David N. Herndon, Donald S. Prough, Perenlei Enkhbaatar University of Texas Medical Branch, Galveston, TX, USA Shriners Hospital for Children, Galveston, TX, USA Background/Purpose: Vascular hyperpermeability and subsequent tissue edema are deleterious complications in sepsis. Arginine vasopressin (AVP) causes vasoconstriction via its V1a receptor agonist effect. However, the role of its V2 receptor (V2R) during sepsis has been poorly studied.We hypothesized that V2R activation during pneumonia sepsis augments vascular leakage, thus promoting cardiopulmonary collapse. We used our well-characterized highly translational ovine methicillinresistant Staphylococcus aureus (MRSA) sepsis model. Methods: Sepsis was induced in 19 surgically instrumented sheep by insufflation of cooled cotton smoke (48 breaths) and instillation of MRSA (3.5 × 10 CFU) into the lungs under anesthesia and analgesia. Grouping: V2R agonist desmopressin (DDAVP, 832.1 ng/kg; n = 6), V2R antagonist tolvaptan (TLVP, 10 mg/kg; n = 6), or saline (control, n= 7), and additional 6 uninjured/untreated sheep (sham, n= 6). All sheep were placed on mechanical ventilation, fluid resuscitated, and monitored for 24 hours in a conscious state. Results: TLVP significantly attenuated systemic fluid accumulation compared to control, while desmopressin tended to augment the MRSA-induced fluid accumulation. Fluid resuscitation to hematocrit was comparable in all groups. TLVP significantly inhibited circulating brain natriuretic peptide and reduced increases in left atrium, pulmonary artery, and lung capillary pressures, suggesting that TLVP attenuatedpulmonary circulation overload and resistance by improving heart performance. DDAVP did not affect these changes. Lung water content (wet-to-dry ratio) was significantly increased in control and DDAVP vs sham. No difference was found between TLVP and sham. Conclusions: Our data strongly suggest that modulation of AVP V2R activation should be considered for treatment of septic patients as an adjunct therapy to various vasopressors. Support: GM097480, SHC84050.