Protamine-induced cardiotoxicity is prevented by anti-TNF-alpha antibodies and heparin.
We investigated the role of tumor necrosis factor alpha (TNF-alpha) in protamine-induced cardiotoxicity and the possibility of preventing or decreasing this effect by anti TNF-alpha antibodies and heparin.



Isolated rat hearts were perfused for 60 min with Krebs-Henseleit solution (KH). The control group was perfused with KH alone, the KH > protamine > KH group was treated from the 20th to the 40th minute with protamine, and the KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF group was treated the same as the KH > protamine > KH group but with anti-TNF-alpha antibodies added throughout perfusion. The KH + heparin > protamine + heparin > KH + heparin group was treated the same as the KH > protamine > KH group but with heparin added to KH throughout perfusion. The KH > protamine > KH + heparin was perfused the same as the KH> protamine > KH group but with heparin added to KH for the last 20 min. Left ventricular (LV) function and coronary flow were measured every 10 min. TNF-alpha was measured in the coronary sinus effluent. Left ventricular TNF messenger RNA was determined in the control and KH > protamine > KH groups at baseline and after the 40-min perfusion.



Protamine caused a significant decrease of peak systolic pressure and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the effluent in the KH > protamine > KH group (102.3 +/- 15.5 pg/min) and TNF messenger RNA expression in left ventricular samples were detected. TNF-alpha was below detectable concentrations in the control, KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF, and KH + heparin > protamine + heparin > KH + heparin groups. TNF-alpha concentrations correlated with depression of LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the increase of LV pressure (r = 0.976; P = 0.001). Heparin improved LV recovery and decreased protamine-induced TNF-alpha release (KH > protamine > KH + heparin group).



Anti-TNF-alpha antibodies and heparin prevent protamine-induced TNF-alpha release and depression of LV function. Heparin improves protamine-induced depression of cardiac function.
Pevni
D
D
Department of Thoracic and Cardiovascular Surgery, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Israel. pevni@tasmc.health.gov.il
Frolkis
I
I
Iaina
A
A
Wollman
Y
Y
Chernichovski
T
T
Shapira
I
I
Paz
J
J
Kramer
A
A
Locker
C
C
Mohr
R
R
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use*; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000627:therapeutic use*; D006494:Heparin Antagonists / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D011479:Protamines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D019138:Antibodies, Blocking; D000925:Anticoagulants; D006494:Heparin Antagonists; D011479:Protamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D006493:Heparin