Trypanosoma cruzi, the protozoan that causes Chagas'
heart disease, invades endothelial cells in vitro by activating the B2
kinin receptor (B2R). 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 (B2R/B1R) antagonists and knockout mice revealed that the early-phase (3-h)
edema is mediated by the constitutive B2R, whereas the late-phase (24-h) response depends on stimulation of the up-regulated B1R. Given previous evidence that parasite invasion of cells expressing B2R is potentiated by
captopril, we investigated the prerequisites for in vitro
infection of Chinese hamster ovary cells overexpressing either B1R or B2R, human umbilical vein endothelial cells activated by
lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that
captopril potentiates parasite invasion regardless of the
kinin (B2/B1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic
acid (MGTA), an inhibitor of
kininase I (
carboxypeptidase M/N), selectively decreases parasite infectivity for B1R-expressing cells. These data suggest that formation of the B1R 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.