Sepsis may lead to deranged
thromboxane-
prostacyclin ratio with consecutive organ dysfunction. Because of the suggested role of the gut in the pathogenesis of
septic shock and
multiple organ failure, we investigated the effects of the novel dual
thromboxane synthase inhibitor and receptor antagonist
DTTX-30 (TRASI) on intestinal tissue perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic, normotensive porcine
endotoxemia. Before, 12, 18, and 24 h after starting continuous i.v.
endotoxin (LPS), we measured portal venous (PV) blood flow, intestinal
oxygen extraction (iO2ER), intracapillary
hemoglobin O2 saturation (HbO2%) of the ileal wall, intramucosal ileal PCO2, PV
lactate-
pyruvate (L-P) ratio, and plasma levels of
thromboxane and
prostacyclin. Treatment with TRASI (0.12 mg/kg i.v. bolus injection followed by an infusion of 0.29 mg/kg/h) initiated after 12 h of LPS infusion markedly reduced the plasma
thromboxane levels and attenuated the LPS-induced fall in systemic vascular resistance, resulting in hemodynamic stabilization. TRASI did not influence the LPS-induced increase in PV blood flow nor intracapillary HbO2%, thus reflecting unchanged microcirculatory O2 availability and decreased iO2ER, possibly because of reduced O2 requirements. Nevertheless, TRASI prevented the LPS-induced increase in the PV L-P ratio, attenuated the progression of the ileal mucosal-arterial PCO2 gap, and tended to attenuate the gradual fall of PV pH. Hence, compounds like TRASI may beneficially influence LPS-related derangements of gut energy metabolism.