THE EFFECT OF SMOKING ON WATER DIURESIS IN MAN 1

Transcription

1 : THE EFFECT OF SMOKING ON WATER DIURESIS IN MAN 1 By J. M. WALKER (From the Department of Pharmacology, Oxford) NICOTINE is the most widely used drug in this country and its effects when continually exerted over years are therefore of medical importance. It is generally known that nicotine stimulates sympathetic ganglia causing a rise of blood-pressure and heart-rate, and various observers (Hesse, 197; Roth, McDonald, and Sheard, 1944) have shown that the amount absorbed from one or two cigarettes is sufficient to raise the blood-pressure by 2 mm and the heart-rate by 1 to 2 beats per minute. Recently a different effect, the liberation of the antidiuretic hormone, has been described by Burn, Truelove, and Burn (1945). Their work followed the demonstration by Pickford (1939, 1947) that acetylcholine injected into dogs inhibited a diuresis produced by giving water by mouth. She proved that acetylcholine exerted its action by stimulating the supra-optic nucleus, for she injected aoetylcholine into the neighbourhood of the nucleus and observed the antidiuretic action only when the injection entered the nucleus. Since this action did not occur after removal of the posterior lobe of the pituitary, Pickford concluded that the acetylcholine stimulated the nucleus to send impulses along the fibres to the posterior lobe, causing a discharge of the hormone. This action of acetylcholine was unaffected by atropine and was therefore a nicotine-like action. It was thus not surprising that Burn and his colleagues found that nicotine itself had the same effect in rats, and that the effect was no longer seen after hypophysectomy. They showed in addition that either the intravenous injection of nicotine or the smoking of one or two cigarettes had a similar antidiuretic action in man. The present work has been done (1) to investigate the variation in the effect of smoking in man in a larger group of subjects, (2) to see whether the antidiuretio action is accompanied by a rise in total chloride excretion, as it should be if due to a liberation of posterior lobe hormone, (3) to estimate the amount of posterior lobe hormone liberated by smoking one or two cigarettes, and (4) to compare the effect of injections of morphine with those of nicotine. Results Diuresis experiments were carried out on 16 students. Each subject emptied his bladder and drank 9 c.o. of warm water. Urine was collected and measured at intervals of 15 minutes, until the final inhibition of diuresis had passed off. The cigarette was smoked, or the injection given, 45 minutes after the subject had drunk the water. 1 Received August 19, [QJ.M. New Series No. 69]

2 52 J. M. WALKER Effect of cigarette-smoking. Out of 13 students seven had an inhibition of diuresis after one cigarette, and the remaining six required two cigarettes to produce an effect. The results are given in Table I. The figures are the number of minutes between the two peaks of diuresis (see figure). It will be seen that of those in whom only one cigarette was effective the majority were nonsmokers, while of those who required two cigarettes to produce an effect the 2 r 15 4 _> O»1 c o E ~ /-" 1 / \ S > -1Z o u ^4 Vz \\ \V Z \i/ A Z- 2^- Z'/i 2 3 / 4 3 Hours The subject drank 9 o.c. of water at zero. He emptied his bladder at 15-min. intervals. The continuous line shows the volume of urine excreted. After 45 mins. he smoked one cigarette, which produced the inhibition shown in the graph. The broken line shows the total chloride excretion. Note the riae in total chloride coincident with the inhibition. majority were smokers. Five students (A, B, C, D, and H) felt slight nausea during the experiments. Change in excretion of total chloride. In Pickford's (1939) experiments the inhibition of diuresis caused by acetylcholine was accompanied by an increased excretion of total chlorides, an effect which is characteristic of the posterior pituitary hormone. In two of the students therefore (Subjects G and J) total chlorides were estimated on each specimen of urine. In both cases there was a rise in total chloride excretion coinciding with the inhibition of diuresis. The result in Subject G is given in the figure. Effect of injections of nicotine. Three students were given intravenous injections of nicotine acid tartrate with the results shown in Table II. It will be seen that the dose of nicotine acid tartrate required to cause an inhibition of diuresis in these subjects was 1-6 to 3* mg. Since the amount of nicotine present in the salt is approximately 5 per cent., it follows that the amount of nicotine required to cause an inhibition of diuresis in the subjects in Table II was from -8 to 1-5 mg. Recently Ling and Wynn Parry have estimated the amount of nicotine which enters the mouth when one cigarette is smoked, and

3 THE EFFECT OF SMOKING ON WATER DIUBESIS IN MAN 53 have found that it lies in the range -66 to 1-2 mg. The amount of nicotine which enters the blood will be the proportion of this which is inhaled. Hence the effect of injected nicotine agrees quantitatively with the effect of nicotine inhaled in the smoke of one or two cigarettes. It is also interesting to note that nausea may accompany the injection of nicotine without there being an inhibition of diuresis (Subject G, dose 2- mg. of nicotine acid tartrate) and also that TABLE I Duration of Inhibition of Water Diuresis by Cigarette-Smoking Subject (N)=non-smoker By one cigarette By two cigarettes (S) = smoker (time in minutes) (time in minutes) Nausea A(N) B(N) C (N) E (S) F (S) G (S) H(S) J (S) K(N) L (S) M(8) N(S) Subject G J O TABLE II Inhibition of Water Diuresis by Nicotine Amount of nicotine Period of inhibition acid tartrate (mg.) (time in minutes) Nausea an inhibition may occur without nausea being felt (Subject J). The inhibition of diuresis must therefore be caused by the nicotine and not merely by nausea. In all three subjects the inhibition of diuresis caused by the injection of nicotine was accompanied by an increased total excretion of chlorides, the peak of chloride excretion coinciding with the inhibition of diuresis. The effect of pituitary (posterior lobe) extract. Injections of pituitary (posterior lobe) extract were given to six students. The results are shown in Table HE, where they can be compared with the effects of cigarette-smoking in the same subjects. The doses of pituitary extract have been expressed in milliunits (md). The ordinary pharmacopoeial extract contains 1 units per c.c. and 1 unit is equal to 1, milliunits. It will be seen that in one case (Subject M) the period of inhibition caused by two cigarettes was almost the same as that caused by 5 mu of pituitary extract intravenously, in three cases (Subjects F, K, and L) one or two cigarettes had less effect than 5 mu, and in two cases (Subjects A and B) one cigarette had a greater effect than 5 mu. The effect of

4 64 J. M. WALKER pituitary extract lasted longer when it was given subcutaneously than when given intravenously. No significant difference could be detected between the effects of 5 and 1 mu given intravenously. The effects of morphine. De Bodo (1944) found that large doses of morphine inhibited water diuresis in dogs. It was of interest therefore to see whether therapeutic doses of morphine had the same effect in man. Seven studente, A B F K L M m m * go 9 6 TABLE A Comparison of the Effects of Cigarette-Smoking and Injections of Pituitary (Posterior Lobe) Extract on Water Diuresis m The figures give the duration of inhibition in minutes By 5 mu of By 1 mu of pituitary extract pituitary extract subcuta- intrave- aubouta- intrave- Subject By one cigarette By two cigarettes ncoudy noudy neously nously minutes after drinking 9 c.c. of water, received a subcutaneous injection of 2 mg. of morphine sulphate, and the effect on diuresis was noted. In no case was there any inhibition of diuresis, which proceeded in a normal manner. It was interesting to note that four of the students suffered from nausea as a result of the injection and of these two were severely affected, and vomited several times. This confirms the conclusion already made from the nicotine experiments, that nausea does not itself necessarily lead to inhibition of water diuresis. Discussion The experiments on cigarette-smoking confirm and extend Burn, Truelove, and Burn's (1945) findings, that the smoking of one or two cigarettes causes an inhibition of water diuresis, and suggest that non-smokers are more susceptible to this effect than habitual smokers (Table I). Nicotine injections, in amounts of the same order as those absorbed from cigarettes, also caused an inhibition of water diuresis (Table II). From Pickford's (1939) work and from Bum, Truelove, and Burn's finding that nicotine did not inhibit water diuresis in rats if the pituitary were removed, it is likely that the inhibiting effect of cigarette-smoking and nicotine is exerted through the pituitary. This is further supported by the fact that in the experiments described in the present paper, the inhibition due to smoking or nicotine injection was accompanied by an increased total excretion of chlorides, an effect characteristic of the action of the posterior lobe hormone. If cigarette-smoking liberates the antidiuretic hormone from the posterior lobe of the pituitary, it is important to know how much hormone is being liberated. Table HI gives the results of injection of

5 THE EFFECT OF SMOKING ON WATER DIURESIS IN MAN 55 pituitary (posterior lobe) extract compared with that of cigarette-smoking. It will be seen that the smoking of one or two cigarettes has an antidiuretic effect of about the same magnitude as that of the intravenous injection of 5 muliunits of pituitary extract. Nausea frequently accompanies smoking and the injection of nicotine, and it is therefore important to know whether the inhibition of diuresis is a non-specific effect of nausea. Table I shows that cigarette-smoking may have an antidiuretic effect even in the absence of nausea. Table II shows that the injection of nicotine may cause nausea without inhibiting diuresis, and may inhibit diuresis without there being any nausea. Finally, the experiments with morphine show that nausea and even vomiting may occur without there being any inhibition of diuresis. The inhibition must therefore be due to the cigarette-smoking or injection of nicotine and not merely to the nausea. Summary 1. Experiments on 13 students showed that an inhibition of water diuresis was caused by the smoking of one cigarette (in seven subjects) and of two cigarettes (in six subjects). Non-smokers were more susceptible to the effect of smoking than smokers. 2. In three students the intravenous injection of 1*6 to 3- mg. of nicotine acid tartrate inhibited water diuresis. 3. The inhibitory effects of smoking and nicotine were both accompanied by a rise in the total chloride excretion and were probably due to the liberation of posterior pituitary hormone. 4. The effect of the smoking was of the same order as that of the intravenous injection of 5 milliunits of pituitary (posterior lobe) extract. 5. There is evidence that the inhibition of water diuresis was not due to a non-specific effect of the nausea that often accompanied smoking or the injection of nicotine. 6. Morphine, in therapeutic doses, does not inhibit water diuresis in man. This work was done during the tenure of a personal grant from the Medical Research Council. REFERENCES Bum, J. H., Truelove, L. H., and Bum, I. (1945) Brit. Med. J. 1, 43. de Bodo, R. C. (1944) J. Pharmacol, and Exper. Therop. 82, 74. Heese, E. (197) Dtsch. Arch. klin. Med. 89, 565. Ling, H. W., and Wynn Parry, C. B. (unpublished). Pickford, M. (1939) J. Phyaiol. 95, 226. (1947) Ibid. 16, 264. Roth, G. M., McDonald, J. B., and Sheard C. (1944) J. Amer. Med. Asa. 125, 761.