Arginine vasopressin receptor 2 activation promotes microvascular permeability in sepsis. (January 2021)

• Record Type: Journal Article
• Authors: Lopez, Ernesto; Fukuda, Satoshi; Modis, Katalin; Fujiwara, Osamu; Enkhtaivan, Baigal; Trujillo-Abarca, Raul; Ihara, Koji; Lima-Lopez, Francisco; Perez-Bello, Dannelys; Szabo, Csaba; Prough, Donald S.; Enkhbaatar, Perenlei
• Is Part Of: Pharmacological research. Volume 163(2021)
• Publication Date: 2021-01
• Subjects: ANGPT2 angiopoietin-2 gene -- AVP arginine vasopressin -- CFU/mL colony forming units per mL -- COHb carboxyhemoglobin -- CT threshold cycle -- CVP central venous pressure -- DDAVP desmopressin -- DMSO dimethyl sulfoxide -- HMVECs microvascular endothelial cells -- HR heart rate -- IP3 inositol 1, 4, 5-trisphosphate -- LAP left atrium pressure -- LDH lactate dehydrogenase -- LR lactated Ringer's -- MAP mean arterial pressure -- MOI multiplicity of infection -- MRSA Methicillin-resistant Staphylococcus Aureus -- normal saline NS -- OD optical density -- OI oxygenation index -- PAP pulmonary artery pressure -- Paw airway pressure -- PcP pulmonary microvascular capillary pressure -- PLCβ4 phospholipase C beta-4 gene -- RT-qPCR real-time polymerase chain reaction -- SI smoke inhalation -- TLVP tolvaptan -- TPA tissue plasminogen activator -- vWF von Willebrand factor -- WBC white blood cells -- W/D wet-to-dry ratio -- WPBs Weibel Palade bodies; Sepsis -- Shock -- Tolvaptan -- Microvascular hyperpermeability -- Endothelium; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105272
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1 R). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (V2 R) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of V2 R activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved V2 R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with V2 R agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the V2 R-induced increase in permeability is mediated by phospholipase C beta (PLCβ) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-V2 R axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.