Post-Exercise Ketosis, Temperature and Dehydration. based on experiments upon aneesthetized animals, usually cats. The actions

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1 Post-Exercise Ketosis, Temperature and Dehydration 361 REFERENCES CAMPBELL, J. and BEST, C. H. (1956). "Physiologic aspects of ketosis", Metabolism, 5, COURTICE, F. C. and DOUGLAS, C. G. (1936). "The effect of prolonged muscular exercise on the metabolism", Proc. roy. Soc. B. 119, DEUEL, H. J. (1957). The Lipids. Their Chemistry and Biochemistry. Vol. III: Biochemistry. New York: Interscience Publishers, Inc. Pp JOHNSON, R. E., SARGENT, F., II and PASSMORE, R. (1958). "The normal variations in total ketone bodies in the serum and urine of healthy young men", Quart. J. exp. Physiol. 43, SARGENT, F., II, JOHNSON, R. E., ROBBINS, EVELYN and SAWYER, LAURA (1958). "The effects of environment and other factors on nutritional ketosis", Quart. J. exp. Physiol. 43, SHAFFER, P. A. (1921). "Antiketogenesis. III. Calculations of the ketogenic balance from the respiratory quotients", J. biol. Chem. 49, TRAPP, H. (1850). Beitriage zur Kenntniss der Verinderungen welche der Urin in Krankheiten erleidet. Thesis, Giessen. Quoted by J. Vogel, Arch. Vereins gemeinschaft. Arbeit. Fdrderung der wissenschaft. Heilkunde, 1, 96. WOODYATT, R. T. (1921). "Objects and method of diet adjustment in diabetes", Arch. intern. Med. 28, THE EFFECTS OF INFUSIONS OF ADRENALINE AND NOR- ADRENALINE ON THE HEART RATE AND ARTERIAL BLOOD PRESSURE OF CONSCIOUS DOGS. By J. A. HOLGATE and W. J. O'CONNOR. From the Department of Physiology, School of Medicine, University of Leeds. (Received for publication 17th April 1958) In conscious dogs infusion of adrenaline at ,ig./kg./min. caused an increase in the heart rate and very little change in arterial blood pressure. Noradrenaline infused in conscious dogs at ,ug./kg./min. caused a decrease in heart rate and an increase in systolic and diastolic arterial blood pressure. The dose of adrenaline which produced an increase in heart rate was thus about one-third that of noradrenaline which produced a decrease in heart rate and an increase in arterial blood pressure. DESCRIPTIONS of the actions of adrenaline and noradrenaline are generally based on experiments upon aneesthetized animals, usually cats. The actions of these substances on the circulation have been studied in conscious human subjects and the results of such experiments have been reviewed by Barcroft and Swan [1953]. Although most of the effects on human subjects are similar to actions previously described in animals, some effects are especially prominent. Clearly, the true physiological functions of adrenaline or noradrenaline circulating in life are more likely to be reflected by intravenous infusions into conscious animals than by rapid injections into anaesthetized

2 362 Holgate and O'Connor animals of doses, often apparently very large. There is, however, no systematic account in the literature of the action of adrenaline and noradrenaline on the circulation of conscious animals other than man, and this gap is partly filled by the results to be presented in this paper. METHODS The results have been obtained from three bitches during experiments in which the effects of adrenaline and noradrenaline on kidney function were also observed. The changes in the urine are reported in another paper [O'Connor, 1958]. At the beginning of each individual experiment a catheter was passed into the bladder and, also, a dose of 0 9 per cent sodium chloride, water or 2-5 per cent urea, was given by stomach tube. The animal was placed on its side on a warm table and, being well accustomed to the procedure, lay quietly for the duration of the experiment. The infusion cannula was inserted into the malleolar vein and infusion of saline begun. Recordings of the blood pressure and heart rate were obtained about every 3 min. for a preliminary period of 20 min. or more; at the same or more frequent intervals during an infusion of adrenaline or noradrenaline lasting min.; then the infusion cannula was withdrawn and observations continued for at least another 30 min. Intravenous infusions were given through a polythene cannula of external diameter 1 mm., bore 0 5 mm., inserted into the malleolar vein and threaded forward about 25 cm. so that the tip of the cannula was in the femoral or iliac vein. The cannula was inserted by using half of a venesection needle cut longitudinally as an introducer [Mitchell, 1952]. The bevelled end of the cannula was fitted within the bevelled, sharp point of the half-needle and the composite "needle" inserted into the vein through a small area anaesthetized with procaine hydrochloride (2 per cent); the half-needle was then slipped back and the cannula threaded forward. The same vein was used repeatedly without complications. The cannula was connected by a twoway tap to two 20-ml. syringes mechanically driven to deliver, usually, 0-26 ml./min. Each syringe contained 0-85 per cent sodium chloride, and one, in addition, the drug; the dose to be infused in each experiment was obtained by an appropriate concentration in the infusion fluid. The final dilution was made up immediately before the experiment, using adrenaline (BDH) dissolved in a small quantity of N/10 hydrochloric acid and noradrenaline bitartrate (Bayer); doses in the text are given in terms of the bases. Aseptic precautions were taken in preparing the solutions and in giving the infusions. Arterial blood pressure was measured in two of the animals ("Skewbald" and "Floss") by the indirect method described by O'Connor [1955]. Systolic and diastolic pressures were determined by means of an oscillometer connected to a pressure cuff applied to the femoral artery previously enclosed in a skin loop, and the heart rate was counted from the oscillometer records. The mean arterial blood pressure was calculated as the diastolic pressure plus one third of the pulse pressure. In the third animal ("Black Sue") a loop was prepared as in the other two, but after about 2 months an abscess developed at the lower end of this loop and the artery returned to a subcutaneous position as the abscess healed. A metal clip was constructed to hold a rubber compression bag and one limb of this clip slipped under the artery by invaginating the loose skin of the groin. When the bag was inflated, pressure was applied to the artery from one side against the metal clip. Satisfactory oscillometer records were obtained, and the changes in blood pressure recorded by this device from "Black Sue" were similar to those in the other animals by a cuff completely surrounding the artery in its skin loop. Electrocardiograms were recorded by leads from the right forelimb, the left forelimb and from the right or left hindlimb. Contact was made by impregnating the short fur of the paw with electrode jelly and bandaging in place a sheet of soft metal from

3 Adrenaline and Noradrenaline 363 which the leads were taken to a lead selector switch. From here the current was fed, after suitable amplification, to a single channel of a four channel ink-recorder (Southern Instruments Limited). RESULTS Adrenaline.-Fig. 1 shows three experiments with "Skewbald" in which adrenaline was infused at 0@034, and 017 Hg./kg./min. In each the heart rate increased by beats/min., and the tachyeardia persisted throughout 14C RATE /min 10c 0~~~~~~~~~~ 64 6 I I '@ I~~~~~~~~~~~ 6C 14C PRESSURE mm Hg 10c I-ml~e%Io 00- I* 0 * ISO~ ~~~~~04 0 S0 000 ḍ 0 o4po'o *.Sga I. I~~~~~~~ Ipooa I 6C MINUTES FIG. 1.-" Skewbald ", 15 kg. The effect of the infusion of adrenaline at (a) 0 034, (b) and (c) 0-17,g./kg./min. Abscissle; time in min. Ordinates: above, pulse rate in beats per min.; below, systolic and diastolic blood pressures in mm. Hg. Adrenaline was infused during the period indicated by the rectangles. the period of the infusion even in instances, not illustrated, when the infusion was continued for 50 min. The oscillometer records and electrocardiograms showed no sign of cardiac irregularity when the rates were high. Thus, in fig. 2, the well marked sinus arrhythmia of the control record was lost during the infusion of adrenaline but the complex of each beat was unaltered. In each of nineteen experiments on " Skewbald " over a period of 4 years, adrenaline always produced a similar tachycardia. Likewise, in the other two dogs, adrenaline always produced an increase in heart rate. In eleven experiments on " Black Sue " there was an increase of beats/min.; in nine experiments on "Floss" the increase in heart rate varied from beats/min. The dose of adrenaline needed to produce tachycardia was of the order of 0 03 pg./kg./min. In the upper half of fig. 3a the increase in heart rate is plotted against the dose of adrenaline infused in thirty-nine experiments on the three dogs; always a large increase in heart rate occurred if the dose was greater than 0*03,ug./kg./min. The full increase characteristic of each group of experiments was produced by infusion of 0 05,g./kg./min. and infusions of doses up to 0-2,ug./kg./min. produced the same effect. The arterial blood pressure was little altered by adrenaline (fig. 1); the systolic and diastolic pressure was determined in fifteen experiments on the three animals and, always, the values obtained during the infusion were

4 364 Holgate and O'Connor within 12 mm. Hg of the values before and after the administration of adrenaline. Fig. lb is an example where there appeared to be a fall chiefly in diastolic pressure during the infusion, but the apparent changes were never more definite than in this example. In the lower frame of fig. 3a any changes in mean blood pressure are plotted against the dose of adrenaline infused, II < 4a LL~ (a) FIG. 2.-" Skewbald", 15 kg. Electrocardiograms taken (a) before and (b) during the infusion of adrenaline at 0-17,g./kg./min. Dog lying on R. side; lead I, from R. forelimb to L. forelimb; Lead II, from R. forelimb to R. hindlimb; lead III, from L. forelimb to R. hindlimb. Vertical bars are 2 millivolts; horizontal bars 1 sec. (b) CHANG-E %*A IN * RAT_E & -i _ *A _ /m i n )XA Ā A ~~~AA ~~~~+40 A x +10- CHANGE A8 IN ~A~0 A.8 (a INFUSION RATE (,pg/kg/min) FIG. 3.-The effects of different rates of infusion of (a) adrenaline and (b) noradrenaline on three dogs. Experiments on " Skewbald " are shown by circles, on ":Floss " by triangles and on "Black Sue" by crosses. Abscissw; rate of infusion (,g./kg./min.). Ordinates: above, change in pulse rate (beats per min.); below, change in mean arterial blood pressure (mm. Hg). and from this it would appear that doses of about 0-1 jtg./kg./min. produced a small fall. Such changes were always less than 12 mm. Hg and are of doubtful significance in view of the limitations of the indirect method of recording the pressure. The effects of adrenaline in conscious dogs may thus be summarized as increase in heart rate with very little change in arterial blood pressure. Noradrenaline.-Fig. 4a, b and c show the results of experiments in which noradrenaline was infused in "Floss" at 0O08, 0O15 and 0 40,ug./kg./min.

5 Adrenaline and Noradrenaline 365 The results in fig. 4b and c are typical of experiments in which noradrenaline was infused in effective doses in the three animals; there was an increase in both systolic and diastolic blood pressure of up to 35 mm. Hg, together with a fall in heart rate of as much as 30 beats/min. In the conscious dog, as in the human subject, noradrenaline thus produced increase in blood pressure and slowing of the heart rate. Fig. 3b shows the effect of noradrenaline in twenty-three experiments on the three animals plotted against the dose infused. The smallest dose of noradrenaline to produce a slowing of the heart and increase in blood pressure 90 RATE /in 5C se,... - K -~1' 20C *a, t. o PRESSURE mm Hg 120 *: S.** 04t'S lo Ao o 9000: IL od 0; 00 I ~~~Io0 8 boo 00 NOd% 000 xi ooo0o I IS MINUTES FIG. 4.-"Floss", 20 kg. The effect of the infusion of noradrenaline at (a) 008, (b) 0-15 and (c) 0-4,tg./kg./min. Abscisse; time in min. Ordinates: above; pulse rate in beats per min.; below, systolic and diastolic blood pressure in mm. Hg. Noradrenaline was infused during the period indicated by the rectangles. was ,ug./kg./min., which was three times the dose of adrenaline needed to produce tachycardia. General Effects.-The infusion of adrenaline at doses up to 0*2 jug./kg./min. and of noradrenaline up to 0-5 jtg./kg./min. produced no restlessness in the dogs. Accustomed to lie quietly on the table, they continued to do so without any indication of the feeling of anxiety which is experienced by human subjects during the infusion of adrenaline [Barcroft and Swan, 1953]. There was no obvious change in respiration, but counts of the respiratory rate were not made. DIsCUSSION The effects of adrenaline and noradrenaline described above are qualitatively similar to the effects produced by the infusion of these substances in human subjects, summarized by Barcroft and Swan [1953, fig. 9, 1]. During infusions of adrenaline in the conscious dogs the increase in heart rate was, however, much greater and more persistant than in human subjects. In the latter tachycardia was maximal about 2 min. after the start of an infusion but then fell and, for the duration of the infusion, remained at a

6 366 Holgate and O'Connor value of about 10 beats/min. above the resting rate [Allen, Barcroft and Edholm, 1946]. In conscious dogs tachycardia persisted unchanged throughout the period of infusion. The changes in arterial blood pressure produced by adrenaline in dogs were much smaller than those found in the human subject by Allen et al. [1946], and the increase in systolic and decrease in diastolic pressure illustrated by Barcroft and Swan [1953] was not observed in our experiments on dogs. The effects of infusions of noradrenaline in conscious dogs were almost identical with those described in man by Barcroft and Konzett [1949]. Our results differ in some respects from the few previous reports of the effects of infusion of these amines in conscious dogs. Pickford and Watt [1951] infused adrenaline and noradrenaline at rates of 2-10,ug./min. in dogs weighing kg. and found that both caused slowing of the heart rate; after atropine adrenaline caused an increase in heart rate while noradrenaline caused a decrease. The experiments of Pickford and Watt were conducted with the animals standing and not lying as in our experiments, and the doses of adrenaline were larger than those we have used. Harries [1956] found complex changes in heart rate, usually slowing, from the infusion of noradrenaline ( itg./kg./min.) in conscious dogs already receiving histamine ( lg./kg./min.). Blake [1955] mentions that there was tachycardia and a transient fall in arterial blood pressure in three experiments in which adrenaline was infused in conscious dogs at 0-28 tug./kg./min. That the effective dose of adrenaline may be smaller than that of noradrenaline is not indicated in the literature. In human subjects, Allen et al. [1946] investigated the effects of the infusion of adrenaline mostly at doses of 10 jlg./min. for 10 min. A few examples are given which indicate that 1,tg./min. had no effect; in one example 3,ug./min. produced an increase in heart rate equal to that produced by 10 jig./min., and the tachyeardia produced by 20 j,g./min. appeared no greater. Barcroft and Konzett [1949] infused adrenaline for shorter periods (3 min.); again, in one example, the tachyeardia produced by 5,ug./min. was as great as that produced by 10, 20 or 30,tg./min. On the other hand, the increase in blood pressure and slowing of the heart rate produced by the infusion of noradrenaline at 5 pkg./min. was less than that produced by 10,ug./min., and the effect of 20 Mg./min. was still greater. It thus appears possible that systematic investigation of the doseresponse relationships in human subjects might reveal that the dose of adrenaline needed to produce tachycardia when infused is less than that of noradrenaline required to produce bradyeardia and increased blood pressure. Goldenberg, Pines, Baldwin, Greene and Roh [1948] stated that infusion of a mixture of equal parts of noradrenaline and adrenaline showed predominantly the effects of adrenaline, while de Largy, Greenfield, McCorry and Whelan [1950] found that infusion of a mixture containing three to eight parts of noradrenaline to one part of adrenaline had no effect on the heart rate of human subjects. The relative activity of the two amines in conscious animals could be of importance in assessing the physiological role of small amounts of the amines liberated into the circulation in normal life.

7 Adrenaline and Noradrenaline 367 ACKNOWLEDGMENT The authors wish to thank Mr. J. Brook for his patient technical assistance. REFERENCES ALLEN, W. J., BARCROFT, H. and EDHOLM, 0. G. (1946). J. Physiol. 105, BARCROFT, H. and KONZETT, H. (1949). J Physiol. 110, BARCROFT, H. and SWAN, H. J. C. (1953). Sympathetic Control of Human Blood Vessels. London: Edward Arnold & Co. BLAKE, W. D. (1955). Amer. J. Physiol. 181, DE LARGY, C., GREENFIELD, A. D. M., MCCORRY, R. L. and WHELAN, R. F. (1950). Clin. Sci. 9, GOLDENBERG, M., PINES, K. L., BALDWIN, E. DE F., GREENE, D. G. and ROH, C. E. (1948). Amer. J. Med. 5, HARRIES, E. H. L. (1956). J. Physiol. 133, MITCHELL, J. V. (1952). Brit. med. J. i, 435. O'CONNOR, W. J. (1955). Quart. J. exp. Physiol. 40, O'CONNOR, W. J. (1958). Quart. J. exp. Physiol. 43, PICKFORD, M. and WATT, J. A. (1951). Quart. J. exp. Physiol. 36, THE EFFECT ON URINARY VOLUME AND COMPOSITION OF THE INGESTION OF 0*9 PER CENT SODIUM CHLORIDE AND OF OCCLUSION OF THE CAROTID ARTERIES. By W. J. O'CONNOR. From the Department of Physiology, School of Medicine, University of Leeds. (Received for publication 17th April 1958) In conscious dogs, changes in the urine following the ingestion of 0-9 per cent sodium chloride presented two different pictures: (a) If no previous doses of sodium chloride had been given, there was an increase in sodium excretion from the resting value of m.equiv/min. up to 0-02 m.equiv/min. because of increased sodium concentration in the urine, without great increase in the urinary volume. Potassium excretion was also increased. (b) If sodium excretion had been raised above 0-02 m.equiv/min. by previous doses of saline, there was a much greater increase in sodium excretion (up to 0 3 m.equiv/min. or more) mainly due to increased urinary volume without any large change in the sodium concentration. Potassium excretion also increased, but no more than in (a) above. The rate of excretion of sodium has been plotted against the fall in the total solid content of the plasma, used as a convenient indicator of the changes in plasma proteins. Fall of the plasma solids by 0-6 g./100 g. below the resting value was associated with a response of type (a) above in which the rate of excretion of sodium increased by m.equiv/min. for each fall of 0.1 g./100 g. in plasma solids. Further fall of plasma solids was associated