The effect of tezosentan, a non-selective endothelin receptor antagonist, on shear stress-induced changes in arterial diameter of the anaesthetized dog

The effects of changes in the mean (S_m) and pulsatile (S_p) components of arterial wall shear stress on arterial dilatation of the iliac artery of the anaesthetized dog were examined in the absence and presence of the endothelin receptor antagonist tezosentan (10 mg kg^-1 I.V.; Ro 61-0612; [5-isopropylpyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy) -5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl) -pyrimidin-4-ylamide]). Changes in shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and stimulation of the left ansa subclavia. An increase in S_m from 1.81 ± 0.3 to 7.29 ± 0.7 N m^-2 (means ± S.E.M.) before tezosentan caused an endothelium-dependent arterial dilatation which was unaffected by administration of tezosentan for a similar increase in S_m from 1.34 ± 0.6 to 5.76 ± 1.4 N m^-2 (means ± S.E.M.). In contrast, increasing the S_p from 7.1 ± 0.8 to a maximum of 11.5 ± 1.1 N m^-2 (means ± S.E.M.) before tezosentan reduced arterial diameter significantly. Importantly, after administration of tezosentan subsequent increases in S_p caused arterial dilatation for the same increase in S_p achieved prior to tezosentan, increasing from a baseline of 4.23 ± 0.4 to a maximum of 9.03 ± 0.9 N m^-2 (means ± S.E.M.; P < 0.001). In conclusion, the results of this study provide the first in vivo evidence that pulsatile shear stress is a stimulus for the release of endothelin from the vascular endothelium.