Cardioprotective effects of phosphoramidon on myocardial structure and function in murine Chagas' disease.
Chagas' disease is an important cause of cardiomyopathy. Endothelin-1, a vasoactive peptide has been implicated in the pathogenesis of chagasic cardiomyopathy. C57BL/6 x 129sv and CD1 mice were thus, infected with trypomastigotes of Trypanosoma cruzi (Brazil strain) and these infected mice were compared with infected mice treated with phosphoramidon. This compound inhibits endothelin-converting enzyme and neutral endopeptidases and does not affect the growth of the parasite in culture. Phosphoramidon was given in a dose of 10mg/kg for the initial 15 days post-infection None of the C57Bl/6 x 129sv mice died as a result of infection. However, there was marked myocardial inflammation and fibrosis in infected, untreated mice. The hearts of the infected, phosphoramidon-treated mice showed significantly less pathology. Cardiac magnetic resonance imaging of infected mice revealed right ventricular dilation that was less severe in those treated with phosphoramidon. Phosphoramidon-treated CD1 mice survived the acute infection. Transthoracic echocardiography demonstrated left ventricular dilation and reduced percent fractional shortening and relative wall thickness. These alterations were also attenuated as a result of phosphoramidon treatment. These data suggest that endothelin-1 contributes to the pathogenesis of chagasic cardiomyopathy and interventions that inhibit the synthesis of endothelin-1 and/or neutral endopeptidase might have a protective effect on myocardial structure and function in murine Chagas' disease.
Jelicks
Linda A
LA
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Chandra
Madhulika
M
Shirani
Jamshid
J
Shtutin
Vitaliy
V
Tang
Baiyu
B
Christ
George J
GJ
Factor
Stephen M
SM
Wittner
Murray
M
Huang
Huan
H
Weiss
Louis M
LM
Mukherjee
Shankar
S
Bouzahzah
Boumediene
B
Petkova
Stefka B
SB
Teixeira
Mauro M
MM
Douglas
Stephen A
SA
Loredo
Maria L
ML
D'Orleans-Juste
Pedro
P
Tanowitz
Herbert B
HB
D000818:Animals; D002598:Chagas Cardiomyopathy / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D005786:Gene Expression Regulation / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000469:parasitology / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014349:Trypanosoma cruzi
D006020:Glycopeptides; D011480:Protease Inhibitors; C008890:phosphoramidon