Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is an important cause of cardiomyopathy. Microvascular spasm and matrix dissolution, modulated by endothelin-1 (ET-1), is implicated in the pathogenesis of chagasic heart disease. To further elucidate the role of ET-1 in murine chagasic heart disease, C57BL/6 x 129sv mice were infected with T. cruzi (10(3) trypomastigotes of the Brazil strain). These mice are resistant to death during the acute phase but progress to chronic cardiomyopathy. Infected mice were compared with infected mice treated with phosphoramidon, a non-specific metalloprotease inhibitor that is also a potent inhibitor of endothelin-converting enzyme, at a dose of 10 mg/kg. Mice were treated with phosphoramidon for the initial 15 days post infection (PI). All mice were evaluated 200 days PI. Examination of infected, untreated mice revealed marked inflammation, vasculitis and fibrosis. The hearts of infected treated mice had significantly less pathology. Cardiac magnetic resonance imaging (MRI) revealed that right ventricular internal diameter (RVID) was significantly greater (P<0.05) in the infected untreated group (2.9+/-0.22 mm) as compared with the infected treated group (1.73+/-0.35 mm). In another experiment phosphoramidon treatment was also tested in CD1 mice, which have a high mortality during the acute phase of infection with 5 x 10(4) trypomastigotes of the Brazil strain. One group of CD1 mice was untreated while the other group received phosphoramidon for the initial 15 days PI. The mortality rate in untreated mice was 70% by day 35 PI, while all treated infected mice lived. The parasitemia in both groups was similar. The cardiac pathology was more severe in untreated mice. MRI revealed the RVID to be significantly greater in the untreated infected group as compared with the phosphoramidon-treated infected mice (2.74+/-0.03 mm versus 1.64+/-0.4 mm P<0.05). Transthoracic echocardiography revealed that the percentage fractional shortening was reduced in infected CD1 mice but not in those infected mice treated with phosphoramidon. There was no effect of phosphoramidon in uninfected mice. Phosphoramidon (100 microg/ml) had no effect on parasites in vitro. These data are consistent with the hypothesis that ET-1 contributes to the pathogenesis of murine chagasic cardiomyopathy and suggests that interventions targeting ET-1 would improve the outcome in chagasic heart disease.
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PMID:Phosphoramidon treatment improves the consequences of chagasic heart disease in mice. 1219 1

Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.
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PMID:Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure. 1515 68

Endothelin, a potent vasoconstrictor first described in 1988 by Yanagisawa, is an important regulator of cardiovascular function. Hyperactivation of the endothelin system has been implicated in the pathogenesis of various cardiovascular disorders including myocardial infarction, restenosis, hypertension, heart failure and Chagas cardiopathy. Various attempts have been made to suppress this axis. Although promising, the results of clinical trials on endothelin receptor antagonists have been disappointing. There is growing interest in blockade of endothelin formation. Several selective and non-selective endothelin-converting enzyme (ECE) inhibitors have been developed, the latter with the possibility of simultaneously blocking angiotensin-converting enzyme and neutral endopeptidase, combining inhibition more than one axis. This article reviews the different ECE inhibitors, with particular emphasis on their potential clinical application in cardiovascular diseases.
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PMID:Endothelin-converting enzyme inhibitors: their application in cardiovascular diseases. 1855 24