The Putative Mechanistic Basis for the Modulatory Role of Endothelin-1 in the Altered Vascular Tone Induced byTrypanosoma cruzi

Abstract

Chagas' disease, caused by Trypanosoma cruzi, is an important cause of heart disease in Latin America. T. cruzi-induced microvascular compromise, in turn, is thought to play a major role in chagasic heart disease. Previous in vitro studies have implicated endothelin-1 (ET-1) as a potentially important vasomodulator present in increased levels in the supernatant of T. cruzi infected cultured human umbilical vein endothelial cells (HUVEC). Thus, the goal of the present investigation was to further evaluate the potentially important contribution of ET-1 to T. cruzi-induced alterations in vascular tone in vitro. Bioassay studies once again documented that exposure of isolated rat aortic rings to infected HUVEC supernatants elicited contractile responses whose steady-state magnitude was significantly greater than contractile responses elicited by exposure of aortic rings to uninfected HUVEC supernatants. Furthermore, the increased aortic contractility was significantly attenuated by the presence of the ET(A) subtype selective antagonists BMS-182,874 or BQ-123. Additionally, incubation of HUVEC with either verapamil or phosphoramidon prior to infection was also associated with reduced aortic contractility, upon exposure to the supernatant. Phosphoramidon, but not verapamil, produced a significant decrease in the measured ET-1 levels in the HUVEC supernatant. Consistent with the bioassay results, preincubation of Fura-2-loaded cultured rat aortic vascular smooth muscle cells with verapamil resulted in a near complete ablation of ET-1-induced transmembrane Ca2+ flux. Taken together, these data are consistent with the hypothesis that ET-1-induced vasoconstriction may play an important modulatory role in the vascular compromise characteristic of T. cruzi infection.

Mechanisms of pathogenesis in Chagas disease

“…Beneficial effects of enzyme inhibition were evidenced by monitoring histopathology, echocardiography, and cardiac magnetic resonance imaging. Moreover, when isolated rat aortic rings were incubated with supernatants from T. cruzi-infected human umbilical vein endothelial cell cultures the recorded steady-state magnitude of the ring contractions was significantly greater than those produced by supernatants from uninfected control cells (Tanowitz et al 1999). All of these observations are consistent with a possible role for ET-1 in inducing vasoconstriction and having a possible modulatory role in the vascular alterations that occur in Chagas heart disease.…”

Application of cardiac gated magnetic resonance imaging in murine Chagas' disease.

“…In addition, verapamil attenuates the endothelin-mediated vasoconstriction accompanying this infection. 19 We then evaluated another murine model of T. cruzi infection, the NOS2 Ϫ/Ϫ mouse. Holscher and others 20 demonstrated that NOS2 mice are rapidly killed by the highly virulent Tulahuen strain of T. cruzi.…”

Role of Endothelin 1 in the Pathogenesis of Chronic Chagasic Heart Disease

“…All of these pathways are crucial in the development of cardiovascular dysfunction. Previous observations from our laboratory and others have implicated ET-1 in the vasculopathy associated with T. cruzi infection (2,31,32,52,57).…”