INCREASED CONCENTRATIONS OF ENDOTHELIN-1 MESSENGER-RNA IN TISSUES ANDENDOTHELIN-1 PEPTIDE IN PLASMA IN SEPTIC PIGS - MODULATION BY BETAMETHASONE

Objectives: To study the expression of preproendothelin-1 messenger RN A (mRNA) in tissue after Escherichia coil lipopalysaccharide challenge and to evaluate the possible effects of betamethasone both regarding endothelin-l production as well as hemodynamic and vascular effects du ring E. coil lipopolysaccharide infusion in pigs in vivo. Design: Pros pective trial, Setting: Laboratory at a university medical center, Sub jects: Ten domestic pigs, weighing 18 to 25 kg, Interventions: Anesthe tized pigs were given continuous infusions of E. coil lipopolysacchari de (15 mu g/kg/hr for 3 hrs), with or without prior treatment with bet amethasone (0.5 mg/kg im 12 hrs before the start of the surgical prepa ration and 0.5/kg iv at the start of the preparation), Measurements an d Main Results: The E. coil lipopolysaccharide infusion evoked the cha racteristic cardiovascular changes observed in septic shock: decreased mean arterial pressure and cardiac output; increased heart rate and i ncreased pulmonary vascular resistance. Large increases in both arteri al plasma con concentrations of endothelin-l-like immunoreactivity, as well as preproendothelin-l mRNA concentrations in tissues, were also observed during the E. coli lipopolysaccharide infusion, Treatment wit h betamethasone significantly attenuated the E. coil lipo polysacchari de induced increase in endothelin-l plasma concentrations, whereas the increased mRNA concentrations were only slightly affected, Furthermor e, betamethasone treatment also affected cardiovascular parameters, wi th significant attenuation of the E. coil lipopolysaccharide-induced i ncrease in heart rate and a higher cardiac output after 60 mins of the E. coil lipopolysaccharide infusion, The urine production, which was markedly decreased during the E. coil lipopolysaccharide infusion, was significantly higher in the betamethasone treated group compared with the control group, Conclusions: The present results indicate that the increased concentrations of endothelin l-like immunoreactivity that a re ob served in septic shock may have negative effects on both cardiov ascular parameters as well as renal function, which is in agreement wi th a possible role for endothelin-l in the pathogenesis of septic shoc k.