title: Protamine releases endothelium-derived relaxing factor from systemic arteries. A possible mechanism of hypotension during heparin neutralization.
abstract: BACKGROUND
  When used to reverse the anticoagulant effect of heparin, protamine sulfate often causes vasodilation that can lead to systemic hypotension. Protamine is rich in the basic amino acid arginine, which is the precursor of endothelial cell synthesis of nitric oxide, and nitric oxide is the active component of endothelium-derived relaxing factor (EDRF).
  
  
  RESULTS
  To determine whether the hypotensive effect of protamine could be due to stimulated release of EDRF, we studied rings (4-5 mm) of canine coronary, femoral, and renal artery suspended in organ chambers containing physiological salt solution (37 degrees C and 95% O2-5% CO2). Arterial rings with and without endothelium were contracted with prostaglandin F2 alpha (2 x 10(-6) M) and exposed to increasing concentrations of protamine (final organ bath concentration, 40-400 micrograms/ml). In arterial segments without endothelium, protamine caused only a modest decrease in tension. However, protamine induced concentration-dependent relaxation in all arterial segments with endothelium, which was significantly greater than in segments without endothelium (p less than 0.05). The endothelium-dependent relaxation induced by protamine was inhibited by NG-monomethyl-L-arginine (L-NMMA) (10(-5) M), but L-NMMA had no effect on rings without endothelium. The action of L-NMMA could be reversed by L-arginine (10(-4) M) but not D-arginine (10(-4) M).
  
  
  CONCLUSIONS
  This study demonstrates that protamine stimulates the release of EDRF from arterial endothelium, and that endothelium-dependent vasodilation may be an important cause of systemic hypotension during protamine infusion.
authors.affiliation: Cardiac Surgical Research, Mayo Clinic, Rochester, Minn 55905.
authors.forename: P J
authors.initials: PJ
authors.lastname: Pearson
authors.forename: P R
authors.initials: PR
authors.lastname: Evora
authors.forename: K
authors.initials: K
authors.lastname: Ayrancioglu
authors.forename: H V
authors.initials: HV
authors.lastname: Schaff
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001158:Arteries / Q000378:metabolism*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects; D006493:Heparin / Q000009:adverse effects* / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced*; D009569:Nitric Oxide / Q000378:metabolism*; D011479:Protamines / Q000009:adverse effects / Q000494:pharmacology*; D013237:Stereoisomerism; D014664:Vasodilation; D019323:omega-N-Methylarginine
chemical_list: D011479:Protamines; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D006493:Heparin; D001120:Arginine