Interaction between paracrine tumor necrosis factor-alpha and paracrine angiotensin II during myocardial ischemia

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 th 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 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.