The influence of the tobacco additives diammonium hydrogen phosphate (DAP) and urea on the delivery and respiratory tract retention of nicotine and solanesol and on the uptake of nicotine into venous blood was investigated in 10 smokers under mouth-hold and 75 and 500 mL inhalation conditions. Three cigarettes with identical physical specifications were produced from a common lamina tobacco blend. The control cigarette contained nonammoniated reconstituted tobacco sheet (RTS), whereas DAP and other ammonia compounds were added to the RTS of the second cigarette. Urea was added to the tobacco of the third cigarette. The presence of DAP or urea in the test cigarettes did not significantly influence solanesol retention within the mouth during the mouth-hold condition. Nicotine retention within the mouth during the mouth-hold condition was, however, significantly higher for the DAP cigarette (64.3 +/- 10.5%) than for the urea (53.3 +/- 11.3%) or control cigarette (46.3 +/- 8.6%), but this did not result in an increase in nicotine uptake into venous blood. Solanesol retentions during the 75 and 500 mL inhalation volume conditions and nicotine retentions during the 75 mL inhalation volume condition were not significantly different for the three cigarette types. Although the nicotine retention approached 100% with each cigarette type during the 500 mL inhalation condition, the nicotine retention for the urea-treated cigarette (99.6 +/- 0.2%) was marginally, but statistically, significant, higher than for the control (99.1 +/- 0.5%) and DAP-treated cigarettes (98.8 +/- 0.6%). There were no statistically significant differences between the indices of nicotine uptake into venous blood for the three cigarette types in any of the inhalation conditions.
The effects of small amounts of nicotine on electrocortical activity and central acetylcholine (ACh) release have been studied on anaesthetized cats.
The most common effect of nicotine given intravenously in a dose of 2 μg/kg every 30 sec for 20 min was to cause desynchronization of the electrocorticogram, indicating cortical activation, and an increase in the release of cortical ACh.
A larger dose given less frequently (4 μg/kg every min for 20 min) caused, in some experiments, an increase and in others a decrease in cortical activity. Such changes were accompanied respectively by an increase or decrease in cortical ACh output.
The amounts of nicotine that affected the electrocorticogram and ACh release are probably similar to those absorbed by the cigarette smoker who inhales.
The effects of nicotine on the electrocorticogram were transient, but the effects on ACh were prolonged. This suggests that at least two pathways are involved in the nicotine response.
The pharmacological actions of chlorpromazine have been described in detail by Courvoisier, Fournel, Ducrot, Kolsky, and Koetschet (1953). This substance was introduced into anaesthetic practice by Laborit and Huguenard (1951) and is given together with promethazine and pethidine, so that it is impossible to know what contribution each makes to the joint effect. We have therefore compared their pharmacological properties quantitatively as well as qualitatively.The properties tested were the power to reduce body temperature; the effect on skeletal muscle stimulated directly and through the nerve; the chronic toxicity; the power to potentiate (a) pentobarbitone, (b) morphine; the anti-adrenaline action; the anti-acetylcholine action; the antihistamine action; and the local anaesthetic action.
METHODS
Body TemperatureEight male mice were used in each experiment, their rectal temperatures being recorded by inserting a lubricated thermocouple into the rectum. This thermocouple was connected to a moving coil galvanometer and the cold junction thermocouple was placed in a constantly stirred water bath at 250 C. The mice were held in position by fastening the tail with adhesive tape to one end of a wire and turning the other end into a loop round the chest. Each mouse was placed in a small celluloid cage of hemispherical cross-section. After half an hour to an hour their temperatures remained steady, and then four mice were used as controls and were injected with saline, while the other four were injected with the substance being tested. The mean difference in temperature between the two groups of mice before the injections was taken as zero and allowance was always made for this difference in calculating the mean temperature-difference between the test mice and the controls recorded at 15-min. intervals.
Skeletal MuscleThe sciatic-gastrocnemius preparation of the cat was used as described by Dale and Gasser (1926). The muscle was stimulated indirectly through the sciatic nerve by rectangular voltage pulses and directly through the muscle by means of induction shocks from a Lewis rotary contact breaker. The rates of stimulation were adjusted so that they were both about 8 or 9/min., and the muscle was continuously stimulated by each method alternately at 1 min. intervals. Injections were made into the right iliac artery close to the bifurcation of the abdominal aorta.The phrenic nerve-diaphragm preparation of the rat was also used. The experimental procedure was the same as that described by Bfilbring (1946), the nerve being stimulated by a pair of platinum electrodes submerged in the organ bath (50 ml.).
Anti-adrenaline ActionThe anti-adrenaline actions of chlorpromazine, promethazine and pethidine were compared on three preparations-the vessels of the rabbit ear, the blood pressure of the spinal cat, and the smooth muscle of the rabbit uterus.(a) Vessels of Rabbit Ear.-The central artery of the rabbit ear was cannulated and injections were made into it by means of the device described by Gaddum and Kwiatkowski (1938)...
Ventricular fibrillation has been studied by driving the ventricles of the isolated rabbit heart electrically and observing whether fibrillation persisted after stimulation was stopped. The hearts were perfused by solutions of different ionic composition and the proportion of hearts in which persistent fibrillation was seen was determined for each solution. The proportion was controlled from 0 to 100 per cent according to the amount of K + , hearts fibrillating spontaneously in .25 N K + . A similar study was made by varying Ca" 1^" . Fibrillation was arrested by ATP and prolonged by dinitrophenol. Fibrillating hearts lost more K + than when they were not fibrillating. Fibrillation appeared to depend on disturbances of the metabolic processes concerned with ion movements.
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