Selective V1a receptor agonist FE 202158 reverses platelet-activating factor-induced hypotension, vascular leak, impaired tissue perfusion, and mortality in rats

Introduction

Platelet-activating factor (PAF) is a phospholipid autacoid inducing peripheral vasodilation and vascular leak, both pathophysiological hallmarks of sepsis-induced cardiovascular dysfunction resulting in hypotension [1]. Indeed, PAF has been implicated in various animal models of sepsis and in septic humans [2]. A deficiency in the vasopressor hormone arginine vasopressin (AVP), a mixed V1a/V2 receptor agonist, also contributes to the cardiovascular dysfunction of septic shock, leading to clinical use of AVP for this condition [3, 4]. These various findings led us to hypothesize that the selective V1a receptor agonist FE 202158 would be effective in a rat model of PAF-induced hypotension.

Methods

Male Wistar rats were anesthetized with thiobutabarbital, surgically instrumented, and put on assisted ventilation. After obtaining baseline data, the mean arterial pressure (MAP) was reduced to 40 mmHg by titration of an intravenous infusion of PAF. Once this level of hypotension was reached, test animals were given an intravenous infusion of FE 202158, titrated to raise and maintain MAP at 70 mmHg for 3 hours while the PAF infusion was continued. Control rats received only an equal infusion of vehicle in addition to the continued PAF infusion.

Results

FE 202158 dramatically reduced mortality in PAF-treated animals compared with PAF + vehicle controls. Survival was 80% in the FE 202158-treated group (8/10) versus 9% in the vehicle-treated group (1/11). Improvements were also observed in other hemodynamic parameters related to vascular leak and tissue perfusion.

Conclusion

This rat model of PAF-induced hypotension reproduced the pathophysiological hallmarks of sepsis-induced cardiovascular dysfunction. The selective V1a receptor agonist FE 202158 was not only able to reverse the associated mortality, but also other manifestations of this dysfunction including vascular leak.