title: Heparin and protamine stimulate the production of nitric oxide.
abstract: Heparin has been shown to decrease total vascular resistance while protamine stimulates endothelium-dependent vasodilation. This study was undertaken to determine whether heparin and/or protamine could enhance endothelium-derived relaxing factor (EDRF), as determined by nitric oxide (NO) production. Porcine carotid artery endothelial cells (PAECs) were seeded on multiwell plates, grown to confluence, and exposed to heparin (1-20 U/ml) or protamine (50-200 microg/ml) for 24 hours. With the addition of the NO synthase inhibitor, N(G)-monomethyl-L-arginine (NMMA), to heparin and/or protamine, the medium samples were collected in one hour. In a parallel clinical study, plasma samples were collected from patients undergoing cardiopulmonary bypass (CPB). The NO production was measured as reflected by the formation of nitrite (NO2-) and nitrate (NO3-), the stable end-metabolites of NO. NO production by PAECs was significantly increased by heparin > or = 5 U/ml or protamine > or = 50 microg/ml in a concentration-dependent manner. The increase of NO production was prevented by the addition of NMMA. In CPB patients, plasma NO2-/NO3- concentration was significantly increased after heparin administration compared to the preoperative value, at which time the mean plasma heparin level was 4.9+/-0.5 U/ml. Following slow protamine infusion, there was no significant difference in plasma NO2-/NO3- concentration compared to preoperative value. In conclusion NO production increases following exposure of PAECs to heparin and/or protamine. In patients, NO concentration significantly increased after heparin administration by IV bolus, but not with a slow infusion of protamine after CPB.
authors.affiliation: Department of Surgery, University of Massachusetts Medical School, Worcester 01655-0333, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Hajarizadeh
authors.forename: C A
authors.initials: CA
authors.lastname: La Rosa
authors.forename: M J
authors.initials: MJ
authors.lastname: Rohrer
authors.forename: T J
authors.initials: TJ
authors.lastname: Vander Salm
authors.forename: B S
authors.initials: BS
authors.lastname: Cutler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002315:Cardiopulmonary Bypass; D002478:Cells, Cultured; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000097:blood; D011479:Protamines / Q000494:pharmacology*; D012189:Retrospective Studies
chemical_list: D011479:Protamines; D009569:Nitric Oxide; D006493:Heparin