However, only one third of septic shock patients suffer from low AVP plasma levels [19]. Typically, endogenous AVP secretion increases in the early phase of septic shock and decreases thereafter. Since V2Rs are involved in several characteristic pathways of septic shock [4-11,20], selective V2R-antagonism rather than V2R-stimulation (for example, via AVP infusion) may be advantageous www.selleckchem.com/products/z-vad-fmk.html under these circumstances.In the present study, AVP plasma levels increased with the onset of septic shock in all groups and remained at this level in the placebo group during the whole study period. The absence of a ‘relative vasopressin deficiency’ may be one reason for the ineffectiveness of AVP in reducing norepinephrine requirements as compared with standard treatment with norepinephrine in the placebo group.

Another potential explanation is that the AVP dose of 0.05 ��g/kg per hour (equivalent to 0.5 mU/kg per minute or 0.035 U/minute in a 70-kg patient) might have been insufficient for the fulminant injury in our model (100% mortality within 17 hours). The latter assumption is in harmony with the observation made in VASST that AVP reduced mortality in less severe septic shock but not in the more severe septic shock population [2]. In this context, Torgersen and colleagues [21] recently reported that, in patients with sepsis-induced vasodilatory shock, a supplementary infusion of 0.067 U/minute AVP was more effective in restoring MAP and reducing norepinephrine requirements than the recommended low dose of 0.033 U/minute.

Interestingly, infusion of the selective V2R-antagonist reduced AVP plasma levels as compared with AVP- and placebo-treated animals. This finding appears to be surprising at first glance. In this context, however, it may be of importance that AVP has a positive feedback on its own release via V2R [22]. Therefore, it is most likely that inhibition of this mechanism has accounted for the low AVP plasma levels noticed in the V2R-antagonist group.Another interesting result of the present study is that the selective V2R-antagonist was as effective as AVP in stabilizing cardiopulmonary hemodynamics without increasing volume and norepinephrine requirements. The reduction in metabolic acidosis by the V2R-antagonist – as suggested by higher pH values, less negative base excess, and lower lactate levels as compared with both other groups – probably reduced systemic vasodilation [23] and contributed to an improved efficacy of norepinephrine by increasing the adrenergic receptor sensitivity [24,25].

In this context, it may also be important that extrarenal V2R mediates vasorelaxant effects [4], thereby decreasing MAP and vascular resistance not only in the experimental setting [26] but also in humans [6,27].In addition, the increased cardiac GSK-3 filling pressures in animals treated with the V2R-antagonist may have improved systemic hemodynamics.