Abstract-The influence of emotional stress on the pharmacokinetics of isosorbide dinitrate (ISDN) was studied in rats. Plasma levels of orally administered ISDN and metabolites (5-isosorbide mononitrate and 2-isosorbide mononitrate) were lower in rats emotionally stressed by foot shock than in non-stressed control rats. The decrease in the ISDN levels may be mainly due to the delay of drug absorption from the gastrointestinal tract.It is generally recognized that the action of drugs is influenced by various factors such as temperature, circumstances, emotinal state and various stresses (1-4). The potentiation or decrease in a drug's effect may be due to changes in the sensitivity of the site of drug action and/or to the pharmacokinetics of the drug. However, there are few reports specifi cally concerned with the influence of emo tional stress on pharmacokinetics.Isosorbide dinitrate (ISDN), a vasodilator, is widely used as an antianginal drug. Angina attacks are often caused by various kinds of stress or effort (5, 6). Almost all patients feel fear or anxiety toward unpredictable attacks. We previously reported that the plasma level of orally administered nicorandil was markedly decreased by applying stress in the form of a foot-shock (7). The present study was designed to determine whether the pharma cokinetics of ISDN would be influenced by emotional stress in rats.Twenty male rats of the Wistar strain weighing 185-220 g were used as the sub jects. They were divided into two groups: the emotionally stressed (ES) group and the non stressed control (C) group. They were housed 3-4 per cage in 26 X 36 X 25 cm plastic walled cages, and they were given food and water ad libitum, except for during the experiment. The animals were maintained on a 12 hr light-dark cycle (lights on 08:00 to 20:00) and at a temperature 22-24 °C and a relative humidity of approximately 60%.previously heated for one day. The column and injector temperature were maintained at 155'C with argon as the carrier gas. The carrier gas was circulated by 10% CH-argon (base) at a pressure of 3.0 kg/cm2.After adding 4 mg of internal standard (isomanide dinitrate, IMDN) to 1 ml of plasma, the plasma was extracted twice with 4 ml of n-hexane. After evaporating to dryness, extracts were reconstituted with 100 ,ul of ethylacetate, and 5 iI was injected into the GC-ECD. To measure 5-ISMN and 2-ISMN, after adding the internal standard to the residue obtained after the above ex traction, the residue was extracted three times with 4 ml of ethylether. The extracts were evaporated and then reconstituted with 100 al of ethylacetate, and 5 ,ul was injected into the GC-ECD.The emotional stress, i.e., foot-shock with pure tone, was given to the animals for 30 min (duration, 10 sec; interval, 90 sec) immediately after the oral administration of ISDN. Foot shock (1.5-2.0 mA) was given for 5 sec after the onset of the pure tone (2000 Hz), which was continued during the foot shock. In the control group, the drug was administered, but the emotional stress was not. Resul...
