Bennett B M, Schröder H, Hayward L D, Waldman S A, Murad F
Department of Medicine, Stanford University School of Medicine, California.
Circ Res. 1988 Oct;63(4):693-701. doi: 10.1161/01.res.63.4.693.
Previously, it was shown that the D enantiomer of isoidide dinitrate was 10-fold more potent than the L enantiomer and 10-fold less potent than glyceryl trinitrate for stimulating cyclic GMP accumulation and relaxation of isolated rat aorta. In the present study, these organic nitrates were tested for their ability to induce tolerance to organic nitrate-induced relaxation, cyclic GMP accumulation, and guanylate cyclase activation in rat aorta in vitro. To compensate for the differences in vasodilator potency, tolerance was induced by incubating isolated rat aorta with concentrations of organic nitrates 1,000-fold greater than the EC50 for relaxation. Under these conditions, the EC50 for relaxation was increased significantly for each organic nitrate and to a similar degree on subsequent reexposure. These data suggest that the potential for inducing in vitro tolerance to relaxation was the same for the three organic nitrates tested. When activation of soluble guanylate cyclase by these compounds was assessed, the enantiomers of isoidide dinitrate were equipotent, but less potent than glyceryl trinitrate, suggesting that the site of enantioselectivity is not guanylate cyclase itself. In blood vessels made tolerant to organic nitrates by pretreatment with glyceryl trinitrate, vasodilator activity, cyclic GMP accumulation, and guanylate cyclase activation were attenuated on reexposure to each organic nitrate. In addition, differences in the potency of the three organic nitrates and the enantioselectivity of isoidide dinitrate for relaxation were abolished in tolerant tissue, whereas the potency difference between glyceryl trinitrate and isoidide dinitrate for activation of guanylate cyclase was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
先前的研究表明，异山梨醇二硝酸酯的D对映体在刺激环鸟苷酸（cGMP）积累和离体大鼠主动脉舒张方面的效力比L对映体高10倍，比三硝酸甘油酯低10倍。在本研究中，测试了这些有机硝酸盐在体外诱导大鼠主动脉对有机硝酸盐诱导的舒张、cGMP积累和鸟苷酸环化酶激活产生耐受性的能力。为了补偿血管舒张效力的差异，通过将离体大鼠主动脉与比舒张EC50高1000倍的有机硝酸盐浓度孵育来诱导耐受性。在这些条件下，每种有机硝酸盐的舒张EC50均显著增加，且在随后再次暴露时增加程度相似。这些数据表明，所测试的三种有机硝酸盐诱导体外舒张耐受性的潜力相同。当评估这些化合物对可溶性鸟苷酸环化酶的激活作用时，异山梨醇二硝酸酯的对映体效力相当，但比三硝酸甘油酯弱，这表明对映选择性的位点不是鸟苷酸环化酶本身。在用三硝酸甘油酯预处理使血管对有机硝酸盐产生耐受性后，再次暴露于每种有机硝酸盐时，血管舒张活性、cGMP积累和鸟苷酸环化酶激活均减弱。此外，在耐受性组织中，三种有机硝酸盐的效力差异以及异山梨醇二硝酸酯对舒张的对映选择性消失，而三硝酸甘油酯和异山梨醇二硝酸酯对鸟苷酸环化酶激活的效力差异未改变。（摘要截断于250字）
