enalapril and Chagas-Disease

Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma cruzi infection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs on T. cruzi infections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The main in vitro findings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γ by T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed in T. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas' disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Captopril; CD8-Positive T-Lymphocytes; Chagas Cardiomyopathy; Chagas Disease; Clinical Studies as Topic; Cytokines; Drug Evaluation, Preclinical; Enalapril; Humans; Losartan; Mice; Trypanosoma cruzi

Trypanosoma cruzi infection triggers a chronic inflammatory process responsible for the alterations in the extracellular matrix and functionality of the heart. The angiotensin converting enzyme (ACE) inhibitors affects T. cruzi in vitro surveillance and modulates in vivo some inflammatory mediators. In this study, we investigated the treatment with an ACE inhibitor (Enalapril) and the Benznidazole (Bz) in a single and combination therapies (CT) in C57BL/6 mice infected with VL-10 strain of the T. cruzi. Animals were treated during 20days with different doses of Bz (100, 80, 60mg/kg), Enalapril (25, 20, 15mg/kg) and their CT (100+25; 80+20; 60+15mg/kg) and euthanized at 30° (acute) and at 120° (chronic) days post infection. The plasma and heart were processed for immunopathological investigations. Our data shown that Bz and Enalapril controlled, in part, the parasite replication and reduced plasma levels of TNF, CCL2 and CCL5 in the acute and in chronic phase of infection. However, the CT doses reduced in around 20% the inflammatory parameters obtained with the Bz therapy. The CT doses of 100+25 and 80+20mg/kg increased the IL-10 levels and reduced the cardiac inflammation while Bz inhibited the collagen neogenesis in the infection. In conclusion, we assume that the CT administrated in the initial stage of infection, presents a minor immunomodulatory effect when the VL-10 strain of T. cruzi is used. In contrast, Bz and Enalapril in monotherapies persist suggesting a potential protection against cardiac damages during experimental T. cruzi infection.

Topics: Animals; Animals, Laboratory; Chagas Disease; Enalapril; Mice; Mice, Inbred C57BL; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi

Chagas heart disease (CHD), caused by Trypanosoma cruzi infection, is a significant cause of morbidity and mortality in South and Central America. Enalapril, an angiotensin converting enzyme (ACE) inhibitor, is an important drug used to ameliorate heart functional capacity and its remodelling in individuals presenting CHD. In this study, we evaluated the effects of enalapril on systemic and cardiac immune response during experimental acute CHD. C57BL/6 mice infected with 50 trypomastigote forms of T. cruzi (Colombian strain) were treated daily with enalapril (25 mg/kg) and, after 30 days, a reduction in seric levels of IFN-gamma, TNF-alpha, CCL5/RANTES and nitric oxide, but not in that of IL-10, was detected. This imbalance of cytokines reflects in a reduction of heart mononuclear infiltration and in an increasing of cardiac mast cells. Enalapril also presents a new and interesting in vitro and in vivo anti-T. cruzi activity probably acting on parasite oxidative pathway via cytochrome-P450. Our data show that enalapril exerts an important anti-T. cruzi and anti-inflammatory activity during acute CHD reducing inflammatory cells and, possibly, preventing fibrotic process in the chronic phase. Nevertheless, further studies are still necessary to clarify the mechanisms by which this drug is acting on the parasites and on the immune pathways.

Topics: Animals; Antiprotozoal Agents; Chagas Cardiomyopathy; Chagas Disease; Cytokines; Enalapril; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Serum; Trypanosoma cruzi