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From the Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Correspondence to J.M. Herbert, Haemobiology Research Department, Sanofi Recherche, 195 Route d'Espagne, 31036 Toulouse, France. E-mail jean-marc.herbert{at}tls1.elfsanofi.fr
Abstract 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 Xainduced relaxations were not affected by hirudin at high
concentrations (1 µmol/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
-nitro-L-arginine methyl ester
(100 µmol/L), whereas relaxations were not altered in the
presence of the inactive enantiomer
N
-nitro-D-arginine methyl ester
(100 µmol/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. Furthermore, 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.
Key Words: rat aorta factor Xa thrombin trypsin endothelium
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