Ulinastatin attenuates protamine-induced cardiotoxicity in rats by inhibiting tumor necrosis factor alpha

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-alpha). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-alpha. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-alpha. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-alpha expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-alpha was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 +/- 4%. In contrast, the reduction in LV dP/dt max was 4 +/- 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-alpha in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-alpha alone reduced LV dP/dt max (- 21 +/- 14%). In contrast, when TNF-alpha was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 +/- 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-alpha synthesis and by directly preventing the cardiodepressant action of TNF-alpha.