Protamine, a polycationic peptide extracted from fish, has been widely used for the reversal of anticoagulant action of heparin. However it may cause untoward circulatory side effects including hypotension and bradyarrhythmia. Nowadays, histamine and prostacyclin are regarded as one of the causative agents in the underlying mechanism of hemodynamic changes. To certify the possible role of histamine and prostacyclin, we observed simultaneous changes of the hemodynamic status, plasma concentration of thromboxane B, and circulating platelet count before and after intravenous injection of protamine. Experimental dogs, weighing 12-14kg, were divided into 2 groups; group A animals [n=10], were pretreated with indomethacin[2.5mg/kg] and group B animals[n=10] were pretreated with chlorpheniramine[0.5mg/kg] Heparin[3mg/kg] and protamine [3mg/kg] were administered sequentially in both groups. The results were as follows ; 1. The mean systemic arterial pressure was maintained well in groups A, whereas in group B it decreased from 165ulcorner18mmHg to 138ulcorner30mmHg[p<0.01] and 151ulcorner21 mmHg[p<0.05] at 1 minute and 2 minutes after protamine injection. The mean pulmonary arterial pressure was not changed significantly in group A, whereas in group B it increased from 852 mmHg to 11ulcorner3 mmHg[p<0.05], 11ulcorner3 mmHg[p<0.05] and 10ulcorner3 mmHg[p<0.05] at 1 minute, 3 minutes and 5 minutes after protamine injection. 2 The thromboxane B2 was not changed significantly in group A, whereas in group B it increased from 399ulcorner401 ulcornerg/ml to 744ulcorner615 ulcornerg/ml[p<0.05] and 814ulcorner1070 ulcornerg/ml [p<0.0 5] at 1 minute and 3 minutes after protamine injection without concomitant changes of pulmonary vascular resistance and pulmonary capillary wedge pressure. 3. The number of circulating platelet was not changed in group A, whereas in group B it decreased from 207100ulcorner103600/ulcornerl to 159700ulcorner90900/ulcornerl [p<0.05] at 1 minute after protamine injection, Although thromboxane B2 and platelet count were changed significantly after protamine injection, they did not cause the remarkable hemodynamic changes. Considering the above results, hemodynamic changes may be caused mainly by prostacyclin rather than thromboxane or platelet. Therefore, the pretreatment with cyclooxygenase inhibitor would be beneficial to prevent circulatory adverse effects of protamine for the patients undergoing cardiac surgery.