Apixaban Enhances Vasodilatation Mediated by Protease-Activated Receptor 2 in Isolated Rat Arteries

Abstract

Apixaban (APX) is a direct inhibitor of factor X (FXa) approved for prophylaxis and treatment of deep venous thrombosis and atrial fibrillation. Because FXa activates protease-activated receptor 2 (PAR-2) in endothelium and vascular smooth muscle, inhibition of FXa by APX may affect vasomotor function. The effect of APX was assessed <i>in vitro</i>, by wire myography, in rat mesenteric resistance arteries (MRAs) and basilar arteries challenged with vasoconstrictors [phenylephrine (PE); 5-hydroxytryptamine (5-HT)], vasodilators [acetylcholine (ACh); sodium nitroprusside (SNP)] or with the PAR-2 peptide agonist SLIGRL. APX (10 μM) reduced the vasoconstriction to PE and 5-HT while did not change the vasodilatation to ACh or SNP. SLIGRL induced concentration-dependent vasodilation in pre-constricted arteries, that was reduced by incubation with the NO inhibitor N^G-nitro-L-arginine (L-NNA) and abolished by endothelium removal. APX enhanced vasodilation to SLIGRL either in the presence or in the absence of L-NNA, but was ineffective in endothelium-denuded vessels. In preparations from heparin-treated rats (to inhibit FXa) APX did not change the vasodilation to SLIGRL. FXa enzymatic activity, detected in mesentery homogenates from controls, was inhibited by APX, whereas APX-sensitive enzymatic activity was undetectable in homogenates from heparin-treated rats. Immunoblot analysis showed that incubation of MRA or aorta with APX increased the abundance of PAR-2, an effect not seen in MRA from heparin-treated rats or in endothelium-denuded aortas. In conclusion, inhibition of FXa by APX increases vasodilatation mediated by PAR-2. APX may act by inhibiting PAR-2 desensitization induced by endogenous FXa. This effect could be useful in the context of endothelial dysfunction associated to cardiovascular diseases.