Coagulation factor Xa induces endothelium-dependent relaxations in rat aorta.
The relaxing effect of coagulation factor Xa on phenylephrine-contracted rat aortic rings was compared with the effect of thrombin and trypsin. All three proteases induced a dose-dependent relaxation in the presence of an intact endothelium. EC50 values were 3 +/- 1, 24 +/- 9, and 16 +/- 1 nmol/L for thrombin, trypsin, and factor Xa, respectively. Whereas thrombin induced rapid relaxations followed by partial recontraction, trypsin and factor Xa induced slower sustained effects. Factor Xa-induced relaxations were not affected by hirudin at high concentrations (1 mumol/L) but were abolished by DX9065A, a specific inhibitor of the catalytic activity of factor Xa. Furthermore, no relaxations to factor Xa could be elicited in the presence of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (100 mumol/L), whereas relaxations were not altered in the presence of the inactive enantiomer N omega-nitro-D-arginine methyl ester (100 mumol/L). Addition of factor Xa together with thrombin induced relaxations that were larger than those induced by thrombin alone, whereas factor Xa had no additional effects on trypsin-induced relaxations. Further-more, factor Xa relaxed thrombin-desensitized aortic rings but was ineffective in trypsin-desensitized tissues. These data suggest that factor Xa acts on a cleavable endothelial receptor that induces NO release, resulting in the relaxation of precontracted rat aortic rings. Factor Xa does not act through endothelial thrombin receptors but may activate another cleavable trypsin-sensitive receptor.
Schaeffer
P
P
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Mares
A M
AM
Dol
F
F
Bono
F
F
Herbert
J M
JM
D000818:Animals; D001011:Aorta / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D015951:Factor Xa / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*
D015951:Factor Xa