Heparin-protamine complexes cause pulmonary hypertension in goats.
BACKGROUND
Protamine reversal of heparin-induced anticoagulation causes thromboxane release followed by pulmonary vasoconstriction in sheep and pigs. The aim of this study was to determine whether heparin-protamine (H-P) complexes are causative agents of thromboxane release followed by pulmonary hypertension associated with protamine reversal of heparin.


METHODS
We separated H-P complexes and non-heparin-protamine (non-H-P) complexes from heparinized defibrinated human plasma neutralized with protamine by chromatography and studied the changes in hemodynamics, airway pressure, and thromboxane B2 concentration after injection of H-P complexes or non-H-P complexes into seven goats. In addition, we studied whether these pulmonary responses were blocked in goats pretreated with cyclooxgenase inhibitor (Indomethacin, n = 5) or thromboxane synthetase inhibitor (OKY-046, n = 5).


RESULTS
A very small dose of H-P complexes increased pulmonary arterial and peak airway pressures and was followed by thromboxane B2 release (from 12 [5.5-23] to 28 [16-44] mmHg, from 9.0 [7.5-15] to 12 [8-19] cmH2O, and from 0.85 [0.34-3.2] to 16.4 [1.4-39.3] ng.ml-1, respectively). On the other hand, animals that received non-H-P complexes showed no significant changes. Indomethacin totally blocked and OKY-046 partially blocked the increases in pulmonary arterial pressure and thromboxane B2 concentration.


CONCLUSIONS
H-P complexes play a major role in pulmonary hypertension after protamine reversal of heparin, and thromboxane A2 is a main mediator of the pulmonary hypertensive response to H-P complexes in goats.
Horiguchi
T
T
Department of Anesthesia, Akita Kumiai Hospital, Japan.
Enzan
K
K
Mitsuhata
H
H
Murata
M
M
Suzuki
M
M
D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D005260:Female; D006041:Goats; D006493:Heparin / Q000633:toxicity*; D006494:Heparin Antagonists / Q000633:toxicity*; D006976:Hypertension, Pulmonary / Q000139:chemically induced*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D011479:Protamines / Q000633:toxicity*; D011651:Pulmonary Artery / Q000187:drug effects; D013929:Thromboxane B2 / Q000096:biosynthesis
D000925:Anticoagulants; D006494:Heparin Antagonists; D008689:Methacrylates; D011479:Protamines; D013929:Thromboxane B2; D006493:Heparin; C034364:ozagrel; D007213:Indomethacin