title: Heparin-enhanced plasma phospholipase A2 activity and prostacyclin synthesis in patients undergoing cardiac surgery.
abstract: Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A2 (PLA2) activity, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) levels were measured at various times during cardiac surgery. Plasma PLA2 activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF1 alpha, TXB2 concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA2 activity, 6-keto-PGF1 alpha, and TXB2 concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA2 activity and plasma 6-keto-PGF1 alpha, but no change in plasma TXB2 concentrations. Thus the ratio of TXB2 to 6-keto-PGF1 alpha increased significantly after protamine administration. Enhanced plasma PLA2 activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA2 was identified as group II PLA2 by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA2 activity and release of PLA2. The PLA2 released from the PMN had characteristics similar to those of post-heparin plasma PLA2. In conclusion, plasma PLA2 activity and 6-keto-PGF1 alpha concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI2) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased plasma PLA2 activity, with an associated increased TXB2/6-keto-PGF1 alpha ratio.
authors.affiliation: Medical Services Massachusetts General Hospital, Boston.
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: D K
authors.initials: DK
authors.lastname: Kim
authors.forename: D M
authors.initials: DM
authors.lastname: Philbin
authors.forename: M B
authors.initials: MB
authors.lastname: Peterson
authors.forename: F
authors.initials: F
authors.lastname: Debros
authors.forename: G
authors.initials: G
authors.lastname: Koski
authors.forename: J V
authors.initials: JV
authors.lastname: Bonventre
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000201:enzymology; D011464:Epoprostenol / Q000096:biosynthesis*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010741:Phospholipases A / Q000097:blood*; D054467:Phospholipases A2; D011479:Protamines / Q000494:pharmacology; D015398:Signal Transduction; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D011479:Protamines; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D006493:Heparin; D011464:Epoprostenol; D010741:Phospholipases A; D054467:Phospholipases A2