Onoue H, Katusic Z S
Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Brain Res. 1998 Feb 23;785(1):107-13. doi: 10.1016/s0006-8993(97)01393-0.
The mechanism underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide is still not completely understood. The present study was designed to determine the role of soluble guanylate cyclase in the relaxations to a nitric oxide/nucleophile complex, diethylaminodiazen-1-ium-1,2-dioate (DEA-NONOate). Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of guanosine 3',5'-cyclic monophosphate (cyclic GMP) were measured by radioimmunoassay technique. During contractions to uridine 5'-triphosphate (UTP), DEA-NONOate (10(-10) to 10(-5) M) caused concentration-dependent relaxations. Measurements of cyclic GMP levels in cerebral arterial wall demonstrated that DEA-NONOate is a potent stimulator of guanylate cyclase and subsequent formation of cyclic GMP. Increasing concentrations of a selective soluble guanylate cyclase inhibitor, 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), caused concentration-dependent reduction of both cyclic GMP production and relaxations to DEA-NONOate. Interestingly, in the presence of the highest concentration (3 x 10(-6) M) of ODQ, production of cyclic GMP in response to 10(-6) M of DEA-NONOate was abolished, whereas the same concentration of DEA-NONOate caused almost complete relaxation, suggesting that mechanisms independent of cyclic GMP production may mediate relaxing effect of high concentration of a nitric oxide donor. A selective Ca2+-activated potassium channel blocker charybdotoxin (CTX) significantly reduced relaxations to DEA-NONOate resistant to ODQ, supporting the idea that in cerebral arteries nitric oxide may activate potassium channels independently of cyclic GMP. The results of our study suggest that under physiological conditions, guanylate cyclase is a key mediator of cerebral arterial relaxations to nitric oxide. However, under pathological conditions associated with induction of nitric oxide synthase and increased biosynthesis of nitric oxide (e.g., cerebral ischemia, inflammation, sepsis), mechanisms other than formation of cyclic GMP may be activated.
大脑动脉平滑肌对一氧化氮产生舒张反应的潜在机制仍未完全明确。本研究旨在确定可溶性鸟苷酸环化酶在对一氧化氮/亲核试剂复合物二乙氨基重氮-1,2-二醇盐（DEA-NO供体）舒张反应中的作用。将无内皮的犬大脑中动脉环悬挂于 Krebs-Ringer 碳酸氢盐溶液中进行等长张力记录。采用放射免疫分析技术测定 3',5'-环磷酸鸟苷（环磷鸟苷）水平。在对尿苷 5'-三磷酸（UTP）产生收缩反应期间，DEA-NO供体（10⁻¹⁰至 10⁻⁵ M）引起浓度依赖性舒张。对大脑动脉壁中环磷鸟苷水平的测量表明，DEA-NO供体是鸟苷酸环化酶的有效刺激剂，并随后促进环磷鸟苷的形成。选择性可溶性鸟苷酸环化酶抑制剂 1H-[1,2,4]-恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）浓度增加，导致环磷鸟苷生成及对 DEA-NO供体舒张反应呈浓度依赖性降低。有趣的是，在最高浓度（3×10⁻⁶ M）的 ODQ 存在下，对 10⁻⁶ M DEA-NO供体的环磷鸟苷生成被消除，而相同浓度的 DEA-NO供体却引起几乎完全舒张，这表明独立于环磷鸟苷生成的机制可能介导高浓度一氧化氮供体的舒张作用。选择性钙激活钾通道阻滞剂蝎毒素（CTX）显著降低对 ODQ 耐药的 DEA-NO供体的舒张反应，支持了在大脑动脉中一氧化氮可能独立于环磷鸟苷激活钾通道的观点。我们的研究结果表明，在生理条件下，鸟苷酸环化酶是大脑动脉对一氧化氮舒张反应的关键介质。然而，在与一氧化氮合酶诱导及一氧化氮生物合成增加相关的病理条件下（如脑缺血、炎症、脓毒症），可能激活除环磷鸟苷形成之外的其他机制。
