title: Complexes of a modified low-molecular-weight heparin with protamine are predominantly cleared by a macrophage scavenger receptor-mediated process in rats.
abstract: Neutralization of heparin with its antidote protamine is associated with side effects such as pulmonary hypertension. The pharmacodynamic effects of protamine treatment are well documented. However, little is known about metabolic fate of heparin-protamine complexes. Twenty Wistar rats received a 131I-labeled low-molecular-weight heparin tracer intravenously. Four groups of animals were formed: a control group receiving the tracer, a second group receiving protamine after tracer application, a third group receiving maleylated bovine serum albumin (mal-BSA) prior to tracer and protamine injections to inhibit scavenger receptors of the reticuloendothelial system, and the last group receiving preformed heparin-protamine aggregates. All animals were examined by scintigraphy. Blood and tissue samples were analyzed for radioactivity. Protamine injection 2 min after heparin tracer application lead to a rapid decline in blood radioactivity. The radioactivity in the liver increased from 17% for the control to 43% after protamine application. Injection of mal-BSA prior to protamine prevented tracer accumulation in the liver and increased urine excretion (34% versus 20%). In vitro preformed heparin-protamine precipitates were rapidly trapped in the liver. We present evidence that, like the polyanionic heparin, polyanionic heparin-protamine complexes are phagocytosed by a scavenger receptor-mediated mechanism by macrophages, predominantly in the liver. The amount, the size, and the charge density of the complexes might trigger a mediator release from macrophages leading to phenomena such as pulmonary hypertension.
authors.affiliation: First Department of Medicine, Faculty for Clinical Medicine, Mannheim, University of Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Stehle
authors.forename: A
authors.initials: A
authors.lastname: Wunder
authors.forename: H
authors.initials: H
authors.lastname: Sinn
authors.forename: H H
authors.initials: HH
authors.lastname: Schrenk
authors.forename: E A
authors.initials: EA
authors.lastname: Friedrich
authors.forename: C E
authors.initials: CE
authors.lastname: Dempfle
authors.forename: W
authors.initials: W
authors.lastname: Maier-Borst
authors.forename: D L
authors.initials: DL
authors.lastname: Heene
mesh_terms: D000818:Animals; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics*; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins; D008657:Metabolic Clearance Rate; D011479:Protamines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
chemical_list: D006495:Heparin, Low-Molecular-Weight; D008565:Membrane Proteins; D011479:Protamines; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B