Blockade of endothelin ETA/ETB receptors favors a role for endothelin during acute Trypanosoma cruzi infection in rats

Abstract: Endothelin has been implicated in the pathogenesis of experimental and human Chagas'' disease (American trypanosomiasis). In the present study, we tested the effect of bosentan, an antagonist of both ETA and ETB endothelin receptors, on parasitemia, histopathology (heart and diaphragm), heart levels of tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon (IFN)-γ, CCL2, CCL3 and CCL5, and the serum levels of nitrate/nitrite (NOx). Bosentan treatment was accompanied by a significant increase in parasitemia and tissue parasitism or inflammation. In vehicle-treated rats, Trypanosoma cruzi infection increased the cardiac levels of TNF-α, IFN-γ and IL-10, at day 9 post inoculation, and the TNF-α remained elevated until day 13. The infection also caused a significant increase in the cardiac levels of the chemokines CCL2 (9, 13 and 18days) and CCL3 (13 and 18days). Bosentan-treatment had no significant effect on the infection-associated increase in IFN-γ and chemokine concentrations. There was a lower increase in IL-10 at day 9 and this was mirrored by a greater increase of TNF-α at day 13, in comparison with vehicle-treated rats. These latter findings correlated well with the enhanced inflammatory process in hearts of bosentan-treated infected rats. Bosentan treatment reduced the infection-associated increase in NOx serum concentration. Altogether, our data suggest that ET action on ETA and ETB receptors may play a role in the initial control of T. cruzi infection in rats probably by interfering in NO production. [Copyright &y& Elsevier]