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EXPERIMENTAL STUDY

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

^a Department of Thoracic and Cardiovascular Surgery, Tel Aviv Medical Center, Tel Aviv, Israel
^b Felsenstein Medical Research Center, Petah Tikva, Israel
^c Department of Nephrology, Tel Aviv Medical Center, Tel Aviv, Israel

Manuscript received August 13, 1999; revised manuscript received July 24, 2000, accepted September 13, 2000.

Reprint requests and correspondence: Dr. Inna Frolkis, Department of Thoracic and Cardiovascular Surgery Tel Aviv Medical Center, 6 Weizman Street, Tel-Aviv 64239, Israel

OBJECTIVES

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 µmol/liter) or losartan (182.2 µmol/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 µmol/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.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   Ang-II = angiotensin II   cDNA = complementary deoxyribonucleic acid   GAPD = glyceraldehyde-3-phosphate dehydrogenase   LV = left ventricular   mAb = monoclonal antibody   mRNA = messenger ribonucleic acid   PCR = polymerase chain reaction   RAS = renin-angiotensin system   TNF-alpha = tumor necrosis factor-alpha

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