Endothelin-1 (ET-1) blockade improves mesenteric perfusion in a porcine low cardiac output model

Background

Various vasomediators regulate the hemodynamic response to acute circulatory failure, including endothelin-1 (ET-1) which is one of the most potent vasoconstrictors known. Mesenteric vasoconstriction reduces the perfusion and oxygenation of the gut mucosa, compromising mucosal barrier integrity. A growing body of evidence links mucosal barrier dysfunction with the development of multiple organ failure (M0F). Improving gut perfusion could preserve mucosal barrier integrity and thus reduce the risk of MOF.

Aim

To investigate if the combined ETA-ETB blocker Ro61-0612 improves gut microcirculation and micro-oxygenation during acute circulatory failure.

Materials and methods

Seven fasted, anesthetised (pentobarbital), mechanically ventilated pigs (30–34 kg) were instrumented to measure cardiac output (CO), portal venous blood flow (QPV; Transonic Systems Inc.), jejunal mucosal microcirculation by laser Doppler flowmetry (LDF, Perimed AB), jejunal tonocapnometry (giving arterial to regional PCO₂ gap, Tonocap, Datex Instruments) and jejuna mucosal micro-oxygenation (tPO₂, Licox, GMS). A pericardial drainage catheter was inserted to establish cardiac tamponade by infusing dextran (reducing QPV to 2/3 of baseline). Measurements were made at baseline (BL), after 90 min of cardiac tamponade (T90) and 90 min following the administration of Ro61-0612 (at 1 mg/kg/h) during tamponade (T90RO). Statistical analyses were made by ANOVA and Fischer's PLSD. A P value < 0.05 was considered statistically significant.

Results

Cardiac tamponade significantly decreased CO, MAP, QPV, LDF, while the pCO₂ gap increased as compared to baseline (BL). The change in tPO₂, failed to gain statistical significance (P = 0.08). Administration of Ro61-0612 increased QPV, LDF, tPO₂ and decreased PCO₂ gap, as compared to T90.

Conclusion

ET-1 blockade in acute circulatory failure improved mesenteric perfusion illustrating the importance of ET-1 induced mesenteric vasoconstriction. Importantly ET-1 blockade restored mucosal blood flow and oxygenation which might be particularly significant considering the implications for maintenance of mucosal barrier integrity.

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