The systemic vasodilatory action of protamine: is it inhibited or mediated by heparin?
The administration of protamine to neutralize the circulating heparin is common practice in cardiovascular surgery. The use of this drug is sometimes associated with hemodynamic alterations of varying degree and intensity (systemic hypotension, pulmonary hypertension and even cardiogenic shock). An intrinsic action of protamine has been suggested to be the cause of these vascular reactions. This action is blocked when protamine forms a complex with heparin, although in other cases it appears that the heparin-protamine complex is the factor responsible for these hemodynamic alterations. The aim of this experimental study was to characterize the vasodilatory action of protamine on the systemic circulation, determining whether or not it is dose-dependent; to analyze the role of endothelium; and to evaluate whether this vasodilatory effect is modified by the presence of heparin.


METHODS
The abdominal aorta was dissected from eight New Zealand rabbits and then sectioned into vascular rings for study in an organ chamber. Mechanical disruption of endothelium was performed on some rings (n = 14). Once submaximal contraction was reached (ClK 80 mM), protamine sulfate with a final concentration in the organ chamber of 80-400 micrograms/ml was added to one of the groups (n = 12). In the second group (n = 12), equal concentrations of protamine were tested in the presence of heparin at a final concentration of 100 U/ml.


RESULTS
The mean vasodilatation reached in the group of rings exposed only to protamine was 95.4 +/- 1.5% with respect to the submaximal contraction induced with ClK. In the second study group, the rings were exposed to protamine at equally increasing concentrations (80-400 micrograms/ml) but with the presence of heparin in the organ chamber. The mean vasodilatation in this group was 90 +/- 1.5. No statistically significant differences in vasodilatation were found between this group and the protamine without heparin group. On the other hand, in the endothelium-denuded rings (n = 14) exposed to isolated protamine and to protamine-heparin, no vasodilatory response was observed.


CONCLUSIONS
Our results show that the administration in vitro of protamine induces endothelium-dependent vasodilatation of the systemic circulation. Likewise, this relaxing effect mediated through endothelium is not blocked when protamine forms a complex with heparin in comparable concentrations of both drugs. Based on these preliminary findings, we believe that in high-risk patients the prevention of systemic vasodilatation and cardiovascular collapse produced by protamine should move towards the use of other substances that can neutralize the anticoagulant effect of heparin or towards pre-medication guidelines that prevent these secondary effects in the case of protamine administration.
Ordoñez Fernandez
A
A
Cardiac Transplant Section, Virgen del Rocio University Hospital, Sevilla, Spain.
Hernandez Fernandez
A
A
Borrego Dominguez
J M
JM
Garcia Tejero
P
P
Perez Bernal
J
J
Hinojosa
R
R
Lopez Hidalgo
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D006494:Heparin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D011189:Potassium Chloride / Q000494:pharmacology; D011479:Protamines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D006494:Heparin Antagonists; D011479:Protamines; D011189:Potassium Chloride; D006493:Heparin; D000109:Acetylcholine