Thromboxane mediation of pulmonary hemodynamic responses after neutralization of heparin by protamine in pigs.
Protamine neutralization of heparin is often associated with severe hemodynamic side-effects, including pulmonary hypertension and systemic hypotension. Because prostanoids may be involved, the authors studied the role of arachidonic acid metabolites, especially thromboxane A2, in this process. During anesthesia with enflurane and fentanyl, four groups of pigs were studied: Group 1 (n = 10) received heparin (250 IU/kg), followed by protamine (100 mg) after 15 minutes to neutralize the heparin. The same protocol was used in group 2 (n = 11), except that the thromboxane A2 receptor antagonist BM 13.177 (10 mg/kg) was infused 5 minutes before the protamine. The protocol for group 1 was also used for group 3 (n = 7) except that these animals were pretreated with indomethacin (10 mg/kg). Animals in group 4 (n = 10) were given protamine only (100 mg). Pulmonary artery pressure and pulmonary vascular resistance increased significantly in group 1 after protamine neutralization of heparin. This was accompanied by significant increases in plasma concentrations of the cyclooxygenase products thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin F2 alpha. Cyclooxygenase products increased to comparable degrees in group 2, but without hemodynamic effects. Leukocyte counts decreased comparably in both groups. Hemodynamic reactions, as well as changes in plasma prostanoid levels were absent in group 3, and group 4, but leukocyte counts were less affected in animals that received protamine alone. The results indicate that the hemodynamic side-effects of protamine are mediated by prostanoids and that thromboxane A2 release is the pivotal step, because side effects were effectively prevented by pretreatment with a thromboxane receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Conzen
P F
PF
Institute of Surgical Research, Ludwig-Maximilians-University, Munich, Bavaria, West Germany.
Habazettl
H
H
Gutmann
R
R
Hobbhahn
J
J
Goetz
A E
AE
Peter
K
K
Brendel
W
W
D000818:Animals; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology*; D006494:Heparin Antagonists; D007213:Indomethacin / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D010976:Platelet Count; D011292:Premedication; D011479:Protamines / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D011651:Pulmonary Artery / Q000187:drug effects; D013552:Swine; D013928:Thromboxane A2 / Q000494:pharmacology*; D014661:Vasoconstriction
D006494:Heparin Antagonists; D011479:Protamines; D013928:Thromboxane A2; D006493:Heparin; D007213:Indomethacin