Effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX-30 on intestinal O2-exchange and energy metabolism during hyperdynamic porcine endotoxemia.
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.
Matejovic
M
M
Sektion Anasthesiologische Pathophysiologie und Vefahrensentwicklung, Universitätsklinik für Anasthesiologie, Ulm, Germany.
Radermacher
P
P
Zülke
C
C
Vlatten
A
A
Altherr
J
J
Brinkmann
A
A
Brückner
U B
UB
Jauch
K W
KW
Georgieff
M
M
Träger
K
K
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002722:Chlorobenzenes / Q000494:pharmacology*; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D007413:Intestinal Mucosa / Q000503:physiopathology*; D007422:Intestines / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects*; D010108:Oxyhemoglobins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013552:Swine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D002722:Chlorobenzenes; C107837:DTTX30; D004731:Endotoxins; D008070:Lipopolysaccharides; D010108:Oxyhemoglobins; D011725:Pyridines; D017482:Receptors, Thromboxane; D002245:Carbon Dioxide; D013930:Thromboxane-A Synthase