扎普司特和谷胱甘肽翻转豚鼠离体气管对硝普钠的耐受性

Zaprinast and glutathione reversed sodium nitroprusside tolerance in guinea pig trachea

上皮完整或去上皮的豚鼠离体气管以３００μｍｏｌ·Ｌ－１硝普钠（ＳＮＰ）预处理１ｈ，使ＳＮＰ对抗乙醋甲胆碱气管收缩作用的剂量反应曲线右移１．３－１．５倍，最大舒张率下降４１％－５８％，形成ＳＮＰ气管松弛作用的耐受性．８－溴环鸟苷酸可模拟ＳＮＰ在豚鼠离体气管形成的ＳＮＰ耐受性，谷胱甘肽（１ｍｍｏｌ·Ｌ－１）及环核苷酸磷酸二酯酶（ＰＤＥ）Ⅴ抑制剂扎普司特（３０μｍｏｌ·Ｌ－１）均可部分翻转ＳＮＰ的气管松弛作用耐受性，而蛋白合成抑制剂环己酰亚胺（１０μｍｏｌ·Ｌ－１）对ＳＮＰ的耐受性无预防作用．结果表明ＳＮＰ可产生豚鼠离体气管松弛耐受性，这可能是由于气管平滑肌中环鸟苷酸（ｃＧＭＰ）积聚而下调鸟苷酸环化酶（ＧＣ）活性和上调ＰＤＥⅤ活性．

Tolerance to sodium nitroprusside (SNP) induced relaxation of guinea pig trachea (intact epithelium or epithelial removal) was developed in vitro. Cumulative SNP concentration relaxation studies were initiated 15 min after tissues were contracted with 3 μmol·L 1 methacholine. Pretreatment of isolated guinea pig tracheal chains with 300 μmol·L 1 SNP for 1 h produced a 1.3-1.5 fold rightward shift of the dose response curve. This shift was associated with a 41%-58% reduction in the maximum SNP induced relaxation. Glutathione (1 mmol·L 1 ) and the phosphodiesterase (PDE) Ⅴ inhibitor zaprinast (30 μmol·L 1 ) partially reversed the tolerance to SNP. However, the protein synthesis inhibitor cycloheximide ( 10 μ mol·L 1 ) did not abolish the tolerance to SNP. These results suggest that tolerance to SNP may be due to cGMP accumulation in tracheal smooth muscle cells, which in turn results in down regulation of guanylate cyclase activity and up regulation of PDE Ⅴ activity.