α 2-Adrenoceptor antagonists evoke endothelium-dependent and - independent relaxations in the isolated rat aorta

Abstract

This study was designed to determine whether the α 2-adrenoceptor antagonists idazoxan, yohimbine, and rauwolscine cause endothelium-dependent and -independent responses in the rat aorta. Rings of rat aorta, with and without endothelium, were suspended for the measurement of isometric force in modified Krebs-Ringer bicarbonate solution (37°C; aerated with 95% O 2 and 5% CO 2). The α 2-adrenoceptor antagonists, in the concentration range of 10 -8-10 -6 M, relaxed phenylephrine-contracted rings with, but not those without endothelium, α 2-Adrenoceptor antagonists (3 x 10 -6 M for 1 min) increased the accumulation of cyclic guanosine monophosphate (cGMP) about twofold in the aortas with endothelium. The relaxation and the increased cGMP induced by α2-antagonists were attenuated by methylene blue (10 -6 M) and N(G)-nitro-L-arginine (L-NA, 3 x 10 -5 M), whereas propranolol (10 -6 M) did not affect the relaxation. In concentrations >10 -6 M, α 2-adrenoceptor antagonists relaxed the rat aorta without endothelium. The endothelium- independent relaxation by α 2-adrenoceptor antagonists was abolished by increased external K + and reduced significantly by tetraethylammonium (TEA, 10 -2 M, a Ca 2+-dependent K + channel blocker), but not inhibited by glibenclamide (10 -5 M, an ATP-sensitive K + channel blocker). In the rabbit aorta, only endothelium-independent relaxations were observed with α2- adrenoceptor antagonists in the concentration range of 10 -8-10 -5 M, and these relaxations were not antagonized by TEA. These results suggest that α 2-adrenoceptor antagonists relax the rat aorta through endothelium- dependent mechanism at lower concentrations and endothelium-independent mechanisms at higher concentrations. The endothelium-dependent relaxations are likely to be mediated by the endothelium-derived relaxing factor (EDRF)/NO pathway because they are associated with the accumulation of cGMP, whereas the endothelium-independent relaxations may be caused by the opening of potassium channels in the vascular smooth muscle.