OBJECTIVES The purpose of this study was to explore interactions between pa
racrine angiotensin II (Ang-II) and tumor necrosis factor-alpha (TNF-alpha)
during myocardial ischemia.
BACKGROUND Ischemic myocardium releases significant amounts of TNF-alpha. T
his paracrine release correlated with postischemic myocardial injury. Other
studies showed myocardial protection obtained by the use of angiotensin-co
nverting enzyme inhibitors (i.e., captopril) and the Ang-II type 1 receptor
antagonist losartan after ischemia. The possibility that these agents decr
ease 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 ca
rdioplegic ischemia. In both groups, either captopril (360 mu mol/liter) or
losartan (182.2 mu mol/liter) was added before ischemia. The hearts were a
ssayed for messenger ribonucleic acid (mRNA) expression and effluent TNF-al
pha levels. In addition, cardiac myocytes were incubated in cell culture wi
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 l
evels were 711 +/- 154 pg/ml. The TNF-alpha mRNA expression declined to 0.4
6 +/- 0.07 (p < 0.01) and 0.65 +/- 0.08 (p < 0.02) in captopril- and losart
an-treated hearts, respectively. Effluent TNF-alpha was below detectable le
vels. Concentrations of TNF-alpha in supernatants of incubated cardiac myoc
ytes 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 m
u mol/liter of losartan, TNF-alpha was below detectable levels.
CONCLUSIONS This study presents an original explanation for previously repo
rted myocardial protection after ischemia, obtained by the use of captopril
and losartan. These drugs reduce TNF-alpha synthesis, providing strong evi
dence of active interactions between paracrine TNF-alpha and Ang-II in the
evolution of the ischemic cascade. CT Am Coil Cardiol 2001;37:316-22) (C) 2
001 by the American College of Cardiology.