Protamine induces endothelium-dependent vasodilatation of the pulmonary artery.
BACKGROUND
Protamine sulfate, which is used for heparin neutralization, has been reported to induce catastrophic pulmonary vasoconstriction after infusion. However, in the systemic circulation, protamine infusion induces hypotension due to peripheral vasodilation.


METHODS
To determine whether protamine also could induce vasodilation in the pulmonary circulation, third-order canine pulmonary artery segments were studied in vitro in organ chambers.


RESULTS
In pulmonary artery segments that were caused to contract with phenylephrine (10(-5) mol/L), protamine sulfate (40 to 400 micrograms/mL, final organ bath concentration) produced concentration-dependent relaxation in canine pulmonary artery segments with endothelium (to 74% +/- 7% of the initial contraction to phenylephrine) that was significantly greater (p < 0.05) than in segments without endothelium (30% +/- 6% of the initial phenylephrine contraction). Pretreatment of arterial segments with NG-monomethyl-L-arginine (10(-5) mol/L), the competitive inhibitor of nitric oxide synthesis from L-arginine, did not change tension of arterial segments, but NG-monomethyl-L-arginine attenuated the relaxation to protamine. The inhibitory effect of NG-monomethyl-L-arginine could be reversed by the addition of L-arginine (10(-4) mol/L) but not D-arginine (10(-4) mol/L). Endothelium-dependent vasodilation to protamine (40 to 400 micrograms/mL) also could be inhibited by heparin (8 U/mL, final organ bath concentration). However, the inhibitory effect of heparin could be overcome by adding higher concentrations of protamine.


CONCLUSIONS
Protamine-mediated pulmonary vasodilatation could be an important mechanism to protect against the constrictive effects of autocoids generated during heparin neutralization. Such a mechanism might be dysfunctional in certain persons and put them at risk for pulmonary vasoconstriction after protamine infusion.
Evora
P R
PR
Section of Cardiovascular Research, Mayo Clinic, Rochester, MN 55905, USA.
Pearson
P J
PJ
Schaff
H V
HV
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011479:Protamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects*
D011479:Protamines; D009569:Nitric Oxide; D006493:Heparin