Thorin E, Huang P L, Fishman M C, Bevan J A
Institut de Cardiologie de Montréal, Centre de Recherche, Quebec, Canada.
Circ Res. 1998 Jun 29;82(12):1323-9. doi: 10.1161/01.res.82.12.1323.
This study was designed to investigate the interaction between the NO/L-arginine pathway and the alpha2-adrenoceptor-mediated endothelium-dependent vasorelaxation. Reactivity of isolated resistance mesenteric arterial segments from mice lacking the gene for constitutive endothelial NO synthase (eNOS- mice, n=14) and from their wild-type controls (WT mice, n=46) was studied in isometric conditions in the presence of indomethacin (blocker of cyclooxygenase). Oxymetazoline (OXY, 0.01 to 30 micromol/L; a selective alpha2-adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS- but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of Nomega-nitro-L-arginine (l-NNA, 100 micromol/L), an inhibitor of NOS, OXY induced an endothelium-dependent relaxation of WT mesenteric arteries. l-NNA had no effect on the relaxation caused by OXY in eNOS- arterial rings. Therefore, the relaxation caused by OXY was independent of NO formation. To demonstrate the inhibitory role of NO on the alpha2-adrenoceptor-mediated relaxation, subthreshold (0.1 nmol/L) to threshold (1 nmol/L) concentrations of sodium nitroprusside (donor of NO) were added to l-NNA-treated arteries before OXY challenges: in these conditions, the alpha2-adrenoceptor-mediated relaxation of eNOS- and WT arteries was inhibited. OXY-induced relaxation was restored on readdition of methylene blue (1 micromol/L, inhibitor of guanylate cyclase), suggesting that cGMP may be the mechanism of inhibition of the alpha2-adrenergic pathway in the presence of NO. Finally, OXY-mediated relaxation was blocked by tetraethylammonium (1 mmol/L) but not glibenclamide (1 micromol/L), suggesting the involvement of an endothelium-derived hyperpolarizing factor that activates Ca2+-activated K+ channels. In conclusion, alpha2-adrenoceptor activation caused relaxation of isolated murine mesenteric arteries that was functionally blocked by NO through a mechanism that may involve activation of the soluble guanylate cyclase and cGMP formation. The endothelium-dependent alpha2-adrenoceptor-mediated relaxation is likely to be due to an endothelium-derived hyperpolarizing factor, whose release and/or production is reduced by concurrent NO formation.
本研究旨在探讨一氧化氮/左旋精氨酸途径与α2-肾上腺素能受体介导的内皮依赖性血管舒张之间的相互作用。在吲哚美辛（环氧化酶抑制剂）存在的等长条件下，研究了缺乏组成型内皮型一氧化氮合酶基因的小鼠（eNOS-小鼠，n = 14）及其野生型对照（WT小鼠，n = 46）分离的肠系膜阻力动脉段的反应性。羟甲唑啉（OXY，0.01至30 μmol/L；一种选择性α2-肾上腺素能受体激动剂）诱导eNOS-动脉而非WT动脉出现内皮依赖性舒张，这些动脉预先用去氧肾上腺素或5-羟色胺收缩。在一氧化氮合酶抑制剂Nω-硝基-L-精氨酸（l-NNA，100 μmol/L）存在的情况下，OXY诱导WT肠系膜动脉出现内皮依赖性舒张。l-NNA对OXY在eNOS-动脉环中引起的舒张无影响。因此，OXY引起的舒张与一氧化氮生成无关。为了证明一氧化氮对α2-肾上腺素能受体介导的舒张的抑制作用，在OXY刺激前，将亚阈值（0.1 nmol/L）至阈值（1 nmol/L）浓度的硝普钠（一氧化氮供体）添加到用l-NNA处理的动脉中：在这些条件下，α2-肾上腺素能受体介导的eNOS-和WT动脉舒张受到抑制。重新添加亚甲蓝（1 μmol/L，鸟苷酸环化酶抑制剂）后，OXY诱导的舒张得以恢复，这表明环磷酸鸟苷（cGMP）可能是一氧化氮存在时抑制α2-肾上腺素能途径的机制。最后，OXY介导的舒张被四乙铵（1 mmol/L）阻断，但未被格列本脲（1 μmol/L）阻断，这表明一种内皮源性超极化因子参与其中，该因子激活钙激活钾通道。总之，α2-肾上腺素能受体激活导致分离的小鼠肠系膜动脉舒张，一氧化氮通过一种可能涉及可溶性鸟苷酸环化酶激活和cGMP形成的机制对其进行功能性阻断。内皮依赖性α2-肾上腺素能受体介导的舒张可能归因于一种内皮源性超极化因子，其释放和/或产生因同时生成的一氧化氮而减少。
