title: Interaction between paracrine tumor necrosis factor-alpha and paracrine angiotensin II during myocardial ischemia.
abstract: OBJECTIVE
  The purpose of this study was to explore interactions between paracrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha) during myocardial ischemia.
  
  
  BACKGROUND
  Ischemic myocardium releases significant amounts of TNF-alpha. This paracrine release correlated with postischemic myocardial injury. Other studies showed myocardial protection obtained by the use of angiotensin-converting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor antagonist losartan after ischemia. The possibility that these agents decrease TNF-alpha synthesis has not yet been investigated.
  
  
  METHODS
  Using the modified Langendorff model, isolated rat hearts underwent either 90 min of nonischemic perfusion (control group) or 1 h of global cardioplegic ischemia. In both groups, either captopril (360 micromol/liter) or losartan (182.2 micromol/liter) was added before ischemia. The hearts were assayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-alpha levels. In addition, cardiac myocytes were incubated in cell culture with Ang-II.
  
  
  RESULTS
  After ischemia, TNF-alpha mRNA expression intensified from 0.63 +/- 0.06 (control group) to 0.92 +/- 0.12 (p < 0.03), and effluent TNF-alpha levels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.46 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losartan-treated hearts, respectively. Effluent TNF-alpha was below detectable levels. Concentrations of TNF-alpha in supernatants of incubated cardiac myocytes treated with 10 and 50 nmol/liter of Ang-II were 206.0 +/- 47.0 pg/ml and 810 +/- 130 pg/ml, respectively (p < 0.004). When pretreated with 700 micromol/liter of losartan, TNF-alpha was below detectable levels.
  
  
  CONCLUSIONS
  This study presents an original explanation for previously reported myocardial protection after ischemia, obtained by the use of captopril and losartan. These drugs reduce TNF-alpha synthesis, providing strong evidence of active interactions between paracrine TNF-alpha and Ang-II in the evolution of the ischemic cascade.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Tel Aviv Medical Center, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Frolkis
authors.forename: J
authors.initials: J
authors.lastname: Gurevitch
authors.forename: Y
authors.initials: Y
authors.lastname: Yuhas
authors.forename: A
authors.initials: A
authors.lastname: Iaina
authors.forename: Y
authors.initials: Y
authors.lastname: Wollman
authors.forename: T
authors.initials: T
authors.lastname: Chernichovski
authors.forename: Y
authors.initials: Y
authors.lastname: Paz
authors.forename: M
authors.initials: M
authors.lastname: Matsa
authors.forename: D
authors.initials: D
authors.lastname: Pevni
authors.forename: A
authors.initials: A
authors.lastname: Kramer
authors.forename: I
authors.initials: I
authors.lastname: Shapira
authors.forename: R
authors.initials: R
authors.lastname: Mohr
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002216:Captopril / Q000494:pharmacology; D002478:Cells, Cultured; D019808:Losartan / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D002216:Captopril; D019808:Losartan