Sun P, Borowitz J L, Kanthasamy A G, Kane M D, Gunasekar P G, Isom G E
Dept. of Pharmacology and Toxicology, Purdue University, West Lafayette, IN 47907-1334, USA.
Toxicology. 1995 Dec 15;104(1-3):105-11. doi: 10.1016/0300-483x(95)03152-6.
In a search for improved cyanide antidotes, the efficacy of isosorbide dinitrate (ISDN), was compared with that of the known cyanide antidote, NaNO2. ISDN was as effective as an optimal dose of NaNO2 in protecting mice against cyanide lethality. To study the mechanism involved, the extent of formation of the cyanide scavenger, methemoglobin, in the action of ISDN was determined. ISDN (300 mg/kg, p.o.) increased methemoglobin from 5 to 10% of total hemoglobin, while, in contrast, NaNO2 (100 mg/kg, i.p.) increased methemoglobin levels to 50% of total hemoglobin. Lowering the dose of NaNO2 to 30 mg/kg reduced methemoglobin levels to approximately 10% of total hemoglobin and in turn nearly abolished its antidotal effect. Decreasing methemoglobin to less than control levels using methylene blue failed to abolish cyanide antagonism by ISDN. Thus, methemoglobin formation by ISDN does not account for its antidotal action. Further studies comparing the respiratory depressant effects of cyanide in the presence of ISDN or NaNO2 also indicated that these two antidotes have different mechanisms of action. Efforts to produce tolerance to the antidotal effect of ISDN against cyanide toxicity were unsuccessful. It is suggested that the well-known ability of ISDN to generate nitric oxide may account for the noted cyanide antagonism.
为寻找更有效的氰化物解毒剂，将硝酸异山梨酯（ISDN）的疗效与已知的氰化物解毒剂亚硝酸钠（NaNO2）进行了比较。在保护小鼠免受氰化物致死方面，ISDN与最佳剂量的NaNO2效果相当。为研究其中涉及的机制，测定了ISDN作用过程中氰化物清除剂高铁血红蛋白的生成程度。ISDN（300mg/kg，口服）使高铁血红蛋白占总血红蛋白的比例从5%增至10%，而相比之下，NaNO2（100mg/kg，腹腔注射）使高铁血红蛋白水平增至总血红蛋白的50%。将NaNO2剂量降至30mg/kg可使高铁血红蛋白水平降至总血红蛋白的约10%，进而几乎消除其解毒作用。使用亚甲蓝将高铁血红蛋白降至低于对照水平并不能消除ISDN对氰化物的拮抗作用。因此，ISDN生成高铁血红蛋白并不能解释其解毒作用。进一步比较ISDN或NaNO2存在时氰化物对呼吸的抑制作用的研究也表明，这两种解毒剂的作用机制不同。使机体对ISDN对氰化物毒性的解毒作用产生耐受性的努力未成功。有人提出，ISDN生成一氧化氮的众所周知的能力可能是所观察到的氰化物拮抗作用的原因。
