Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

Abstract

IntroductionV2-receptor (V2R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V2R-antagonist (Propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V1aR/V2R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock.MethodsAfter the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V2R-antagonist (1 μg/kg per hour), AVP (0.05 μg/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 μg/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary.ResultsCompared to AVP- and placebo-treated animals, the selective V2R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V2R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V2R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V2R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V2R-antagonist group. In addition, the selective V2R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025).ConclusionsSelective V2R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.

Selective V1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

“…This assumption is supported by a study of Traber (48) who showed that vascular leakage is promoted by V 2 -receptor stimulation in an ovine model of pneumonia-induced sepsis. The relevance of V 1a -receptor selectivity is further emphasized by an experimental trial reporting that a selective V 2 antagonist reduced metabolic, liver, and renal dysfunction as compared with norepinephrine and AVP in an ovine model of peritonitis-induced septic shock (39).…”

Bench-to-bedside review: Vasopressin in the management of septic shock

“…Rehberg and colleagues designed a clever study in which they gave a V2 receptor antagonist (propionyl-1-d-(Tyr(Et)2-Val4-Abu6-Arg8,9)-vasopressin) with or without a V1a agonist (arginine vasopressin) or placebo to chronically instrumented sheep who had early septic shock [137]. This V2 receptor antagonist with arginine vasopressin maintained hemodynamics (cardiac index and MAP) and increased the left ventricular stroke work index.…”

Terlipressin or norepinephrine in septic shock: do we have the answer?

“…Terlipressin is a synthetic analogue of vasopressin which has greater affinity for the V1 receptor that is the mechanism of vascular smooth muscle vasoconstriction in response to vasopressin and thus could be associated with less side effects than vasopressin (7). Animal model studies have shown similar vasoconstrictive efficacy with terlipressin vs. vasopressin and less fluid retention with terlipressin which is critical for septic shock patients.…”