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BASIC SCIENCE STUDY

Effect of tumor necrosis Factor-Alphaon endothelial and inducible nitric oxidesynthase messenger ribonucleic acidexpression and nitric oxide synthesisin ischemic and nonischemic isolated rat heart

Yosef Paz, MD^*, Inna Frolkis, MD, PhD^*,*, Dimitri Pevni, MD^*, Itzhak Shapira, MD^*, Yael Yuhas, PhD, Adrian Iaina, MD, Yoram Wollman, PhD, Tamara Chernichovski, MSc, Nahum Nesher, MD^*, Chaim Locker, MD^*, Rephael Mohr, MD^* and Gideon Uretzky, MD^*

^* Department of Thoracic and Cardiovascular Surgery, Tel-Aviv University, Tel-Aviv, Israel
Department of Nephrology, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Felsenstein Medical Research Center, Petah-Tikva, Israel

Manuscript received February 3, 2003; revised manuscript received May 19, 2003, accepted June 4, 2003.

^* Reprint requests and correspondence: Dr. Inna Frolkis, Department of Thoracic and Cardiovascular Surgery, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
frolkisi{at}tasmc.health.gov.il

OBJECTIVES: The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-) that was synthesized during ischemia and exogenous TNF- on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart.

BACKGROUND: Tumor necrosis factor- is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF--induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF--induced myocardial dysfunction is highly controversial.

METHODS: Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF- on the expression of eNOS mRNA and iNOS mRNA and on NO production.

RESULTS: After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 ± 0.08 to 0.68 ± 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF- had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 ± 0.04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels.

CONCLUSIONS: We believe this is the first study to directly show that TNF- does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.

Abbreviations and Acronyms   CF = coronary flow   eNOS = endothelial nitric oxide synthase   iNOS = inducible nitric oxide synthase   KH = Krebs-Henseleit   LV = left ventricular   mRNA = messenger ribonucleic acid   NO = nitric oxide   NOS = nitric oxide synthase   PCR = polymerase chain reaction   TNF- = tumor necrosis factor-alpha

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