Increased prostacyclin and adverse hemodynamic responses to protamine sulfate in an experimental canine model.
Prostanoid activity was correlated with the hemodynamic effects of protamine sulfate reversal of heparin in 24 dogs undergoing three different pretreatment regimens: Group I (n = 8) received saline, Group II (n = 8) received the thromboxane synthetase inhibitor U63,557A (30 mg/kg), and Group III (n = 8) received indomethacin (10 mg/kg). Pretreatment substances were administered as 5-min intravenous infusions 20 min before anticoagulation with intravenous heparin (150 IU/kg). Protamine sulfate (1.5 mg/kg) was subsequently given as a 10-sec intravenous infusion 30 min after heparin had been administered. Hemodynamic data, as well as prostacyclin (PGI2) and thromboxane (TxA2) activity in aortic, venous, and pulmonary artery blood samples, were assessed over a 30-min time period following protamine administration. Group III indomethacin pretreatment provided the most protection from declines in blood pressure, heart rate, cardiac output, venous oxygen saturation, oxygen consumption, and elevations in pulmonary pressures and was accompanied with actual declines in PGI2. Group II U63,557A pretreatment was associated with the most severe hemodynamic changes and the greatest increase in PGI2 (+576%). Elevated PGI2 correlated with hypotension at 1 and 3 min (P less than 0.01), as well as pulmonary artery pressure declines at all times following protamine reversal. TxA2 changes did not correlate with hemodynamic changes. Protamine's adverse hemodynamic responses were attenuated with cyclooxygenase blockade by indomethacin, but were worsened with selective TxA2 blockade with U63,557A. Excess arachadonic acid precursors in the latter setting may increase PGI2 production. This study, for the first time, raises the possibility that PGI2 contributes to the adverse effects accompanying protamine reversal of heparin anticoagulation.
Wakefield
T W
TW
Jobst Vascular Research Laboratories, Department of Surgery, University of Michigan, Ann Arbor 48109.
Wrobleski
S K
SK
Wirthlin
D J
DJ
Wang
T W
TW
Stanley
J C
JC
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D004285:Dogs; D011464:Epoprostenol / Q000097:blood*; D006439:Hemodynamics / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D011479:Protamines / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000097:blood; D014680:Veins
D001572:Benzofurans; D011479:Protamines; D013931:Thromboxanes; D009599:Nitroprusside; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; C039936:furegrelate; D010100:Oxygen; D007213:Indomethacin