Zygmunt P M, Högestätt E D, Grundemar L
Department of Clinical Pharmacology, Lund University, Sweden.
Acta Physiol Scand. 1994 Oct;152(2):137-43. doi: 10.1111/j.1748-1716.1994.tb09793.x.
Acetylcholine (ACh) induces an N omega-nitro-L-arginine (L-NOARG)-resistant relaxation and hyperpolarization in the rat isolated hepatic artery. The possibility that carbon monoxide (CO) produced by haem oxygenase (HO) is an endogenous mediator of this response was investigated. Exogenously applied CO evoked a concentration-dependent relaxation, and the CO 'scavenger' oxyhaemoglobin (10 microM) reduced the maximum ACh-induced relaxation by 25%. The HO inhibitor zinc protoporphyrin IX (ZnPP, 10 microM) virtually abolished the ACh-induced relaxation in experiments carried out under ordinary light conditions. However, ZnPP did not affect the ACh-induced relaxation under dark conditions, even after exposure of ZnPP to intense light before the preincubation period. Biliverdin (0.1 mM), a feedback inhibitor of HO, was also inactive under dark conditions, and the HO substrate haematin (0.1 mM) did not facilitate the ACh-induced relaxation. The relaxation induced by the nitric oxide (NO) donor 3-morpholino-sydnonimin was not affected by ZnPP in the presence of light. However, ZnPP inhibited the relaxation evoked by the potassium channel opener levcromakalim and the tonic component of the contractile response to 60 mM potassium, indicating that ZnPP has effects distinct from HO inhibition in the presence of light. ZnPP should therefore be protected from light when used to inhibit HO-mediated CO formation. The results do not suggest that CO generated by HO mediates the endothelium-dependent, L-NOARG-resistant relaxation induced by ACh in the rat hepatic artery.
乙酰胆碱（ACh）可诱导大鼠离体肝动脉产生对Nω-硝基-L-精氨酸（L-NOARG）耐药的舒张和超极化。研究了血红素加氧酶（HO）产生的一氧化碳（CO）作为这种反应内源性介质的可能性。外源性应用CO可引起浓度依赖性舒张，CO“清除剂”氧合血红蛋白（10 μM）使ACh诱导的最大舒张降低25%。在普通光照条件下进行的实验中，HO抑制剂锌原卟啉IX（ZnPP，10 μM）几乎完全消除了ACh诱导的舒张。然而，即使在预孵育期之前将ZnPP暴露于强光下，ZnPP在黑暗条件下也不影响ACh诱导的舒张。HO的反馈抑制剂胆绿素（0.1 mM）在黑暗条件下也无活性，HO底物血红素（0.1 mM）也不能促进ACh诱导的舒张。在有光的情况下，一氧化氮（NO）供体3-吗啉代-西多硝胺诱导的舒张不受ZnPP影响。然而，ZnPP抑制了钾通道开放剂左旋克罗卡林引起的舒张以及对60 mM钾收缩反应的张力成分，表明ZnPP在有光的情况下具有不同于抑制HO的作用。因此，在用于抑制HO介导的CO形成时，ZnPP应避光保存。结果并不表明HO产生的CO介导了ACh在大鼠肝动脉中诱导的内皮依赖性、L-NOARG耐药性舒张。
