Schröder H, Noack E
Institute of Pharmacology, University of Düsseldorf, F.R.G.
Arch Int Pharmacodyn Ther. 1987 Dec;290(2):235-46.
The effect of different organic nitrates on the activity of soluble guanylate cyclase prepared from rat liver was investigated. We found a close correlation between the number of nitrate ester groups and the potency of guanylate cyclase activation. For erythrityl tetranitrate (ETN, EC50 = 14.5 microM), glyceryl trinitrate (GTN, EC50 = 60 microM), isoidide dinitrate (IIDN, EC50 = 0.24 mM) and isosorbide-5-nitrate (IS-5-N, EC50 = 1 mM), we were able to set up an equation by which the EC50 could be calculated from the number of nitrate groups per molecule. Compared to these results, the effect of sterical factors and lipophilicity on organic nitrate-induced activation of guanylate cyclase was small. However, there were still significant differences in the EC50 values for the cyclic mononitrates. Isosorbide-2-nitrate (IS-2-N, EC50 = 0.75 mM) was found to be more potent than the stereoisomeric isosorbide-5-nitrate. Similarly, the cyclic dinitrates isomannide dinitrate (IMDN, EC50 = 0.20 mM), isoidide dinitrate and isosorbide dinitrate (ISDN, EC50 = 0.28 mM) exhibited small but significant differences in their guanylate cyclase stimulatory potency. Two lipophilic ester derivatives of isosorbide-5-nitrate showed a 2-fold potency difference for vasodilation but were equipotent for activation of guanylate cyclase (EC50 = 0.85 mM). Also, the increase in lipophilicity due to esterification of the free hydroxylic group had no major influence on guanylate cyclase activation by isosorbide-5-nitrate. These results demonstrate that in a cell-free system, the potency of organic nitrates for guanylate cyclase activation is mainly determined by the number of nitrate groups. Since organic nitrate-induced activation of guanylate cyclase may involve the formation of nitric oxide free radicals, it is conceivable that the differences in potency reflect a varying degree of nitric oxide release from each compound tested.
研究了不同有机硝酸盐对从大鼠肝脏制备的可溶性鸟苷酸环化酶活性的影响。我们发现硝酸酯基团的数量与鸟苷酸环化酶激活的效力之间存在密切相关性。对于四硝酸赤藓醇（ETN，EC50 = 14.5 microM）、三硝酸甘油酯（GTN，EC50 = 60 microM）、异山梨醇二硝酸酯（IIDN，EC50 = 0.24 mM）和5-硝酸异山梨酯（IS-5-N，EC50 = 1 mM），我们能够建立一个方程，通过该方程可以根据每个分子的硝酸基团数量计算EC50。与这些结果相比，空间因素和亲脂性对有机硝酸盐诱导的鸟苷酸环化酶激活的影响较小。然而，环状单硝酸酯的EC50值仍存在显著差异。发现2-硝酸异山梨酯（IS-2-N，EC50 = 0.75 mM）比立体异构体5-硝酸异山梨酯更有效。同样，环状二硝酸酯异甘露醇二硝酸酯（IMDN，EC50 = 0.20 mM）、异山梨醇二硝酸酯和异山梨醇二硝酸酯（ISDN，EC50 = 0.28 mM）在其鸟苷酸环化酶刺激效力上表现出微小但显著的差异。5-硝酸异山梨酯的两种亲脂性酯衍生物在血管舒张方面表现出2倍的效力差异，但在激活鸟苷酸环化酶方面效力相当（EC50 = 0.85 mM）。此外，由于游离羟基酯化导致的亲脂性增加对5-硝酸异山梨酯激活鸟苷酸环化酶没有重大影响。这些结果表明，在无细胞系统中，有机硝酸盐激活鸟苷酸环化酶的效力主要由硝酸基团的数量决定。由于有机硝酸盐诱导的鸟苷酸环化酶激活可能涉及一氧化氮自由基的形成，可以想象效力的差异反映了每种测试化合物释放一氧化氮的程度不同。
