ANTAGONISM OF CYANIDE TOXICITY BY ISOSORBIDE DINITRATE - POSSIBLE ROLE OF NITRIC-OXIDE

In a search for improved cyanide antidotes, the efficacy of isosorbide dinitrate (ISDN), was compared with that of the known cyanide antidot e, NaNO2, ISDN was as effective as an optimal dose of NaNO2 in protect ing mice against cyanide lethality. To study the mechanism involved, t he extent of formation of the cyanide scavenger, methemoglobin, in the action of ISDN was determined. ISDN (300 mg/kg, p.o.) increased methe moglobin from 5 to 10% of total hemoglobin, while, in contrast, NaNO2 (100 mg/kg, i.p.) increased methemoglobin levels to 50% of total hemog lobin. Lowering the dose of NaNO2 to 30 mg/kg reduced methemoglobin le vels to approximately 10% of total hemoglobin and in turn nearly aboli shed its antidotal effect. Decreasing methemoglobin to less than contr ol 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 th at these two antidotes have different mechanisms of action. Efforts to produce tolerance to the antidotal effect of ISDN against cyanide tox icity were unsuccessful. It is suggested that the well-known ability o f ISDN to generate nitric oxide may account for the noted cyanide anta gonism.