Premium
Arginine Vasopressin Receptor 2 (V 2 R) Acti vation Disrupts Endothelial Barrier and Promotes Vascular Hyper‐permeability
Author(s) -
Lopez Ernesto,
Fujiwara Osamu,
Enkhtaivan Baigalmaa,
Zhu Yong,
PerezBello Dannelys,
Rojas Jose,
Cox Robert,
Hawkins Hal,
Herndon David,
Prough Donald,
Enkhbaatar Perenlei
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.789.7
Subject(s) - medicine , agonist , vasopressin , sepsis , desmopressin , vasopressin receptor , endocrinology , antagonist , receptor
Arginine vasopressin (AVP) is used in sepsis as an adjuvant vasopressor due to its effect as an AVP V 1a receptor agonist, but high dose of AVP is associated with detrimental side effects. We hypothesized that V 2 R activation in endothelial cells promotes vascular hyper‐permeability. Methods: We used our conscious ovine sepsis model, in which pneumonia was induced by smoke inhalation and airway instillation of 3.5X10^11CFU Methicillin‐resistant Staphylococcus aureus ( MRSA). V 2 R agonist, desmopressin (DDAVP) or antagonist, tolvaptan (TLVP) were the studied treatments. In parallel, we studied human lung microvascular endothelial cells (HMVECs), which express V 2 R. Confluent cells were treated with DDAVP (.3, 1, 3, 10, or 30 nM) during 12 hrs of continuous recording of electrical impedance. Further studies were done with DDAVP 30 nM. V 2 R and Angiopoietin 2 (Ang‐2) mRNA expression was also measured. Results: TLVP treatment prevented accumulation of fluids and improved survival. A decrease in urinary output was also observed with DDAVP.Table 1: A total of 26 mechanically ventilated sheep were randomly allocated into 4 groups and monitored in a conscious state during 24 hrs Group Injury Treatment Fluid Input (mL) Urinary Output (mL) Fluid Acumulation (mL) Hematocrit Survival Sham, n=6 no Injury Vehicle 2327 ±814 2366 ±684 54 ±245 27 ±2 6/6 Control, n=8 SI+MRSA Vehicle 7273 ±2031 # 3268 ±591 4419 ±2286 # 27 ±3 4/8 TLVP, n=6 SI+MRSA Tolvaptan, 416.6 ug/kg/h 4606 ±432 3623 ±788 983 ±935* 28 ±2 5/6 DDAVP, n=6 SI+MRSA Desmopressin, 36.16 ng/kg/h 6837 ±1517 # 2165 ±486 § 4672 ±1369 #§ 29 ±1 6/6 Mean ± SEM. Two Way ANOVA: * P< 0.05 vs Control, # p<0.05 vs Sham, § p< 0.05 vs TLVP. Continuous infusion of drugs started 1 hour post‐ injury. Fluid resuscitation was titrated to hematocrit. Urine output was measured via Foley catheterIn HMVECs, the electrical impedance decreased with 3, 10 and 30 nM DDAVP for 30 min (p>0.001). Permeability was also impaired with DDAVP.Peroxynitrite, VEGF and MRSA increased V 2 R expression similar to DDAVP (p>0.05). HMVECs treated with DDAVP had increased Ang‐2 expression. Conclusion V 2 R activation mediates vascular hyper‐permeability during sepsis. High dose of AVP should be avoided or adjunct V 2 R antagonist should be considered for treatment of septic patients. NIH RO1 GM097480, SHC 85500 and SHC 84050.