Differences in threshold for protamine toxicity in isolated atrial and ventricular tissue.

The inotropic and chronotropic effects of protamine sulfate on rabbit myocardium were studied using isolated preparations of atrial and ventricular tissue. Each tissue differed markedly in its susceptibility to depression of peak isometric developed tension. The threshold concentration for depression of tension was 0.022% for left atrium, 0.055% for right atrium, and 0.3% for right ventricular papillary muscle. Tension in the left atrial preparation increased 20% over control at a protamine concentration of 0.02%, but decreased to less than 30% of control at a concentration of 0.022%. Right atrial tissue tension decreased to 48% of control at a protamine concentration of 0.055% and then to 17% of control at a concentration of 0.6%. In papillary muscle, tension decreased to 64% of control at a concentration of 0.3% and then to 9% of control at a concentration of 0.35%. Thus a very steep dose-response curve was observed for each tissue. In the right atrium-sinoatrial node preparation, administration of protamine at concentrations of 0.05-0.06% produced intermittent atrial extrasystoles, but no significant change in overall rate of discharge. The narrow margin of safety of the protamine dose-response curve may provide a partial explanation for the precipitous nature of hypotensive episodes during clinical administration.