Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin receptor subtypes (B 1 /B 2 )

Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades endothelial cells in vitro by activating the B2 kinin receptor (B 2 R). Here, we demonstrate that mice infected with trypomastigotes develop potent edema after treatment with the angiotensin‐converting enzyme (ACE) (or kininase II) inhibitor captopril. Experiments performed with specific kinin receptor (B 2 R/B 1 R) antagonists and knockout mice revealed that the early‐phase (3‐h) edema is mediated by the constitutive B 2 R, whereas the late‐phase (24‐h) response depends on stimulation of the up‐regulated B 1 R. Given previous evidence that parasite invasion of cells expressing B 2 R is potentiated by captopril, we investigated the prerequisites for in vitro infection of Chinese hamster ovary cells overexpressing either B 1 R or B 2 R, human umbilical vein endothelial cells activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that captopril potentiates parasite invasion regardless of the kinin (B 2 /B 1 ) activation pathways, whereas DL‐2‐mercaptomethyl‐3‐guanidino‐ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase M/N), selectively decreases parasite infectivity for B 1 R‐expressing cells. These data suggest that formation of the B 1 R agonist, i.e., [des‐Arg] kinins, critically depends on the processing action of kininase I, here proposed as a potential pathogenesis cofactor. Collectively, our data suggest that fluctuations in the levels of kininases may modulate parasite infectivity and pathological outcome in Chagas' disease.