EFFECTS OF PROTAMINE ON MYOCYTE CONTRACTILE FUNCTION AND BETA-ADRENERGIC RESPONSIVENESS

The use of protamine sulfate in patients has been associated with seve re circulatory collapse and myocardial failure. However, the exact mec hanisms responsible for these reactions to protamine remain unclear. A ccordingly, we examined the effect of protamine on isolated myocyte co ntractile function. Indexes of isolated myocyte contractile function, percent shortening, and velocity of shortening were examined using vid eomicroscopy. Porcine cardiocytes (n = 75) were studied at baseline an d in the presence of 80 mu g/mL protamine. In addition, myocyte functi on was examined sequentially, first during treatment with 8 IU/mL hepa rin and then after the addition of a protamine dose sufficient to comp letely bind the heparin. The binding of heparin and protamine resulted in the formation of a heparin-protamine complex. The protamine concen tration of 80 mu g/mL is approximately equal to the serum concentratio n of protamine obtained in patients when administered in a dose of 5 m g/kg. In the presence of 80 mu g/mL protamine, both percent shortening and velocity of shortening fell by more than 32% from baseline values (p < 0.05). The presence of either heparin alone or the heparin-prota mine complex resulted in no change in baseline myocyte contractile mea surements. Furthermore, to examine the effect of protamine on myocyte beta-adrenergic responsiveness a second series of experiments were per formed. Myocyte contractile function was measured when 25 nmol/L isopr oterenol was added to each of the protocols above. The presence of 80 mu g/mL protamine resulted in a significant blunting of myocyte beta-a drenergic responsiveness. The presence of either heparin alone or the heparin-protamine complex resulted in no change in myocyte beta-adrene rgic responsiveness. In summary, the presence of unbound protamine but not the heparin-protamine complex resulted in depressed baseline myoc yte contractile function and blunted myocyte beta-adrenergic responsiv eness. This study demonstrated that unbound protamine can directly dep ress myocyte contractile performance. Thus, one potential mechanism fo r the alteration in hemodynamics and left ventricular function that ca n occur after the administration of protamine is the direct depressant effect of unbound protamine on myocyte contractile function.