α2-Adrenoceptor Antagonists Evoke Endothelium-Dependent and -Independent Relaxations in the Isolated Rat Aorta

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Abstract
This study was designed to determine whether the α2-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% O2 and 5% CO2). The α2-adrenoceptor antagonists, in the concentration range of 10−8-10−6M, relaxed phenylephrine-contracted rings with, but not those without endothelium. α2-Adrenoceptor antagonists (3 × 10−6M 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 (10−6M) and NG-nitro-L-arginine (L-NA, 3 × 10−5M), whereas propranolol (10−6M) did not affect the relaxation. In concentrations >10−6M, α2-adrenoceptor antagonists relaxed the rat aorta without endothelium. The endothelium-independent relaxation by α2-adrenoceptor antagonists was abolished by increased external K+ and reduced significantly by tetraethylammonium (TEA, 10−2M, a Ca2+-dependent K+ channel blocker), but not inhibited by glibenclamide (10−5M, 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 10−8-10−5M, and these relaxations were not antagonized by TEA. These results suggest that α2-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.