Rb. Hird et al., EFFECTS OF PROTAMINE ON MYOCYTE CONTRACTILE FUNCTION AND BETA-ADRENERGIC RESPONSIVENESS, The Annals of thoracic surgery, 57(5), 1994, pp. 1066-1075
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.