Protamine-induced Cardiotoxicity Is Prevented by Anti-TNF-α Antibodies and Heparin |
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Authors: | Pevni, Dmitry M.D. Frolkis, Inna M.D., Ph.D. Iaina, Adrian M.D. Wollman, Yoram Ph.D. Chernichovski, Tamara Ms.C. Shapira, Izhak M.D. Paz, Josef M.D. Kramer, Amir M.D., Ph.D. Loker, Chaim M.D.
Mohr, Rephael M.D. |
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Affiliation: | Pevni, Dmitry M.D.*; Frolkis, Inna M.D., Ph.D.*†; Iaina, Adrian M.D.‡; Wollman, Yoram Ph.D.‡; Chernichovski, Tamara Ms.C.‡; Shapira, Izhak M.D.*; Paz, Josef M.D.*; Kramer, Amir M.D., Ph.D.*; Loker, Chaim M.D.§; Mohr, Rephael M.D.* |
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Abstract: | Background : 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. Methods : 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. Results : 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). |
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