Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis

Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2596-603. doi: 10.1152/ajpheart.00215.2008. Epub 2008 Apr 11.

Abstract

The cardiac natriuretic peptides atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are discoordinately regulated in myocardial inflammation associated with acute allograft rejection in humans and during in vitro exposure of cardiocyte cultures to some proinflammatory cytokines. We used experimental autoimmune myocarditis (EAM) to determine whether the discoordinate regulation of ANF and BNP was specific to the situations above or was generally associated with other types of myocardial inflammation. The dependency of this process to angiotensin signaling was also determined, given that previous work demonstrated beneficial effects of the angiotensin receptor blocker olmesartan in myocarditis. Histopathological changes, plasma and cardiac ANF, BNP, and selected cytokines gene expression as well as plasma cytokine levels using a cytokine array were determined in EAM, angiotensin receptor blocker-treated, and control rats. It was found that EAM specifically increases BNP but not ANF circulating levels, thus mimicking the findings in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures in vitro. Plasma cytokine array and real-time PCR revealed that lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-1 were increased in plasma and in the myocardium of EAM rats. Olmesartan treatment reversed virtually all neuroendocrine and histopathological cardiac changes induced by EAM, thus providing a mechanistic insight into this phenomenon. It is concluded that the inflammatory process contributes specific cytokines, leading to the disregulation of cardiac ANF and BNP production observed during myocardial inflammation, and that this process is angiotensin receptor 1 dependent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Atrial Natriuretic Factor / metabolism
  • Blood Pressure / drug effects
  • Cytokines / blood
  • Disease Models, Animal
  • Imidazoles / pharmacology*
  • Mycobacterium tuberculosis
  • Myocarditis / drug therapy*
  • Myocarditis / metabolism
  • Myocarditis / microbiology
  • Myocarditis / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Natriuretic Peptide, Brain / blood
  • Natriuretic Peptide, Brain / genetics
  • Natriuretic Peptide, Brain / metabolism*
  • Polymerase Chain Reaction
  • Protein Array Analysis
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred Lew
  • Receptor, Angiotensin, Type 1 / drug effects*
  • Receptor, Angiotensin, Type 1 / metabolism
  • Tetrazoles / pharmacology*
  • Up-Regulation

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Cytokines
  • Imidazoles
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Natriuretic Peptide, Brain
  • Atrial Natriuretic Factor
  • olmesartan