COAGULATION-FACTOR XA INDUCES ENDOTHELIUM-DEPENDENT RELAXATIONS IN RAT AORTA

The relaxing effect of coagulation factor Xa on phenylephrine-contract ed rat aortic rings was compared with the effect of thrombin and tryps in. All three proteases induced a dose-dependent relaxation in the pre sence of an intact endothelium. EC50 values were 3+/-1, 24+/-9, and 16 +/-1 nmol/L for thrombin, trypsin, and factor Xa, respectively. Wherea s thrombin induced rapid relaxations followed by partial recontraction , trypsin and factor Xa induced slower sustained effects. Factor Xa-in duced relaxations were not affected by hirudin at high concentrations (1 mu mol/L) but were abolished by DX9065A, a specific inhibitor of th e catalytic activity of factor Xa. Furthermore, no relaxations to fact or Xa could be elicited in the presence of the NO synthase inhibitor N -omega-nitro-L-arginine methyl ester (100 mu mol/L), whereas relaxatio ns were not altered in the presence of the inactive enantiomer N-omega -nitro-D-arginine methyl ester (100 mu mol/L). Addition of factor Xa t ogether with thrombin induced relaxations that were larger than those induced by thrombin alone, whereas factor Xa had no additional effects on trypsin-induced relaxations. Furthermore, factor Xa relaxed thromb in-desensitized aortic rings but was ineffective in trypsin-desensitiz ed tissues. These data suggest that factor Xa acts on a cleavable endo thelial receptor that induces NO release, resulting in the relaxation of precontracted rat aortic rings. Factor Xa does not act through endo thelial thrombin receptors but may activate another cleavable trypsin- sensitive receptor.