Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: Modulation by betamethasone

Objectives: To study the expression of preproendothelin-1 messenger RNA (mRNA) in tissue after Escherichia coli lipopalysaccharide challenge and to evaluate the possible effects of betamethasone both regarding endothelin-l production as well as hemodynamic and vascular effects during E. coli lipopolysaccharide infusion in pigs in vivo. Design: Prospective trial, Setting: Laboratory at a university medical center, Subjects: Ten domestic pigs, weighing 18 to 25 kg, Interventions: Anesthetized pigs were given continuous infusions of E. coli lipopolysaccharide (15 mu g/kg/hr for 3 hrs), with or without prior treatment with betamethasone (0.5 mg/kg im 12 hrs before the start of the surgical preparation and 0.5/kg iv at the start of the preparation), Measurements and Main Results: The E. coli lipopolysaccharide infusion evoked the characteristic cardiovascular changes observed in septic shock: decreased mean arterial pressure and cardiac output; increased heart rate and increased pulmonary vascular resistance. Large increases in both arterial 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 with betamethasone significantly attenuated the E. coli lipo polysaccharide induced increase in endothelin-l plasma concentrations, whereas the increased mRNA concentrations were only slightly affected, Furthermore, betamethasone treatment also affected cardiovascular parameters, with significant attenuation of the E. coli lipopolysaccharide-induced increase in heart rate and a higher cardiac output after 60 mins of the E. coli lipopolysaccharide infusion, The urine production, which was markedly decreased during the E. coli 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 are ob served in septic shock may have negative effects on both cardiovascular parameters as well as renal function, which is in agreement with a possible role for endothelin-l in the pathogenesis of septic shock.