Research for the role of endothelium-dependent relaxation in the change of maternal circulation during pregnancy

我们在大鼠后肢血流灌注模型中观察了NO和/或EDHF在降低外周血管阻力中的作用，并分析了EDHF在该模型中的同一性。卡巴胆碱(CCH)产生松弛的能力与硝普钠(SNP)在数量上相似。内皮剥脱后CCH诱导的松弛作用消失，但对硝基精氨酸和消炎痛有抵抗作用。四乙基铵、哇巴因、河豚毒素和阿帕明均能抑制这种松弛，且在去极化状态下。SNP诱导的松弛伴随着cGMP产生的增加，而cGMP的产生被ODQ抑制。虽然卡巴胆碱的松弛程度与SNP相似，但cGMP水平比SNP低24倍。低KCI引起一定的松弛，这种松弛可被哇巴因抑制，但不依赖于NO、前列环素和内皮细胞。1-EBIO作为IK通道的激动剂，也产生浓度依赖性的松弛作用，这种松弛作用可被白纹藻毒素、哇柏…抑制更多的氮和去极化，但不依赖于NO和前列环素。克霉唑和十八烷基环酸作为P_(450)&gt；单加氧酶的阻断剂，可抑制氨基甲胆碱引起的松弛。而过氧化氢酶在足以抑制H_2O_2诱导的松弛时，对氨甲酰胆碱诱导的松弛没有明显的抑制作用。这些结果提示，卡巴胆碱具有内皮依赖性、EDHF依赖性和NO-cGMP非依赖性的松弛作用，K~+和P&lt；450&gt；单加氧酶的代谢物(S)可能在这种松弛中起重要作用。我们还研究了妊娠期间后肢外周阻力血管的反应性是否发生了变化，并利用大鼠后肢灌流模型，从药理学角度分析了NO和EDHF对这些变化的贡献。在妊娠末期，我们的模型外周血管阻力降低。外周血管阻力的增强是由EDHF介导的，部分原因是cGMP生成下游通路的敏感性增加，可能导致大鼠足月妊娠时血压降低和对血管收缩药的低反应性。较少

We examined the involvement of NO and/or EDHF in decreasing peripheral vascular resistance in hind limb perfusion model of the rat, and analyzed the identity of EDHF in this model. The potency of carbachol (CCh) to produce relaxation was quantitatively similar to sodium nitroprusside (SNP). CCh-induced relaxation was abolished after endothelial denudation, but resistant to nitroarginine and indomethacin. The relaxation was inhibited by tetraethylammonium, ouabain, charybdotoxin plus apamin and under depolarization. SNP-induced relaxation was accompanied by the increased cGMP production, which was inhibited by ODQ. Although carbachol produced similar extent of relaxation to SNP, cGMP level was 24 times lower than that with SNP. Low KCI produced a definite relaxation, which was inhibited by ouabain, but independent of NO, prostacyclin and endothelium. 1-EBIO as an activator of IK_<Ca> channel also produced a concentration-dependent relaxation, which was inhibited by charybdotoxin, ouabai … More n and depolarization, but independent of NO and prostacyclin. Clotrimazole and 17-octadecynoic acid as inhibitors of P_<450> mono-oxygenase inhibited the carbachol-induced relaxation. Meanwhile, catalase at a concentration sufficient to inhibit H_2O_2- induced relaxation did not exert definite inhibition of the carbachol-induced relaxation. These results suggest that carbachol produces an endothelium-dependent, EDHF-dependent and NO-cGMP independent relaxation and that K^+ and metabolite(s) of P_<450> mono-oxygenase possibly play an important role for this relaxation. We also we investigated whether the responsiveness of peripheral resistant vessels of the hind limb changes during pregnancy, and the contribution of NO and EDHF to these changes was pharmacologically analyzed using a hind-limb perfusion model of the rat. In the end stage of pregnancy, peripheral vascular resistance was decreased in our model. The enhanced decrease in the peripheral vascular resistance, which is mediated by EDHF and partly due to the increased sensitivity of the pathway downstream the cGMP generation, possibly results in lowering the blood pressure and hyporesposiveness to vasoconstrictors at the term gestation of the rat. Less