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

我们在大鼠后肢灌注模型中检测NO和/或EDHF在降低外周血管阻力中的作用，并分析EDHF在该模型中的身份。碳醇（CCh）产生松弛的效力在数量上与硝普钠（SNP）相似。cch诱导的松弛在内皮剥脱后消失，但对硝基精氨酸和吲哚美辛有抗性。四乙基胺、瓦沙因、白藜芦醇毒素加维生素和去极化抑制了弛豫。snp诱导的松弛伴随着cGMP的增加，而ODQ抑制了cGMP的产生。虽然carbachol产生与SNP相似的松弛程度，但cGMP水平比SNP低24倍。低KCI产生明确的松弛，可被瓦巴因抑制，但不依赖于NO、前列环素和内皮素。1-EBIO作为IK_<Ca>通道的激活剂也产生了浓度依赖性的弛豫，这种弛豫被白肉毒素、白肉毒素和去极化抑制，但不受NO和prostacycyclin的影响。氯霉唑和17-十八环酸作为P_<450>单加氧酶抑制剂抑制了碳甾醇诱导的松弛。同时，过氧化氢酶在足以抑制H_2O_2-诱导的松弛时，对碳甾醇诱导的松弛没有明显的抑制作用。这些结果表明，碳乙醇产生内皮依赖性、edhf依赖性和NO-cGMP依赖性弛豫，而P_<450>单加氧酶的K^+和代谢物可能在这种弛豫中起重要作用。我们还研究了妊娠期间大鼠后肢外周耐药血管的反应性是否发生变化，并利用大鼠后肢灌注模型从药理学角度分析了NO和EDHF在这些变化中的作用。在妊娠末期，我们的模型外周血管阻力降低。EDHF介导的外周血管阻力的增强降低，部分原因是由于cGMP下游通路的敏感性增加，可能导致大鼠妊娠期血压降低和对血管收缩剂的反应降低。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