A Bipolar Theory of Living Processes

Normal response of the brain to adrenalin. In normal rabbits the intravenous injection of adrenalin was followed by a rise in the temperature of the brain which in most instances amounted to between 0.3 and 0.5? ©., although in some instances an even greater rise occurred. The rise started immediately after the injection, the highest point being reached in from 6 to 10 minutes, with an approximately equally protracted return to the temperature level preceding the injection.

Response of the brain to adrenalin in anesthetized animals. In rabbits under ether anesthesia the temperature of the brain rose abruptly upon the injection of adrenalin, and the rise was usually greater than in normal animals. Under nitrous ovid anesthesia, on the other hand, there was slight or no response to the injection of adrenalin or the response was atypical. In one experiment the injection of adrenalin in an animal anesthetized with urethane caused an abrupt rise in the temperature of the brain followed by a delayed decline.

Response of the brain to adrenalin in iodized animals. The injection of adrenalin in animals which had been iodized by the intraperitoneal injection of iodoform produced an abrupt increase in the temperature of the brain which was greater than that observed in any other condition—in one instance amounting to 1.72° C. within 4 minutes with an equally abrupt fall. Response of other organs than the brain to the injection of adrenalin. The liver is apparently irresponsive to the injection of adrenalin as far as is indicated by temperature variations.

The thyroid gland, on the other hand, showed a response to adrenalin in temperature variations which in some cases approximately paralleled the temperature changes in the brain. The temperature of voluntary muscle apparently is not changed The effect of hepatectomy upon the response of the brain to adrenalin. Repeated observations appeared to demonstrate that after hepatectomy the power of the brain to respond to adrenalin By accident, however, it was found that if even a very small portion of the liver remained patent to the circulation, the brain would register its usual response to adrenalin by the typical increase in temperature. In this experiment, it appeared at first that the premise we had thought established by preceding hepatectomies was disproved, until autopsy revealed that a small lobe of the liver had not been included in the ligation. Subsequent experiments have verified this finding.

A single experiment was performed to see whether or not lack of response of the brain of a hepatectomized animal was due to lack of glucose. In this experiment, at least, no effect upon the response to adrenalin was produced by the intravenous injection of a solution of glucose in a hepatectomized animal. The effect of thyroidectomy upon the response of the brain to adrenalin. Forty-eight hours after the removal of both thyroids the injection of adrenalin was followed by a delayed and slight rise in the temperature of the brain.

1. The temperature of the brain and of the thyroid was increased by adrenalin. 2. The temperature of the liver and of voluntary muscle was not affected by the injection of adrenalin. 3. In the absence of the liver the injection of adrenalin produced a diminished or no change in the temperature of the brain. 4. In the absence of the thyroid the reaction of the brain to adrenalin was diminished. 5. In iodized animals the reaction of the brain to adrenalin appeared more promptly and was greater than in normal animals.

6. In animals under ether anesthesia the reaction of the brain to adrenalin was greater than in normal animals. 7. In animals under nitrous ovid anesthesia the reaction of the brain to adrenalin was delayed and diminished. 1. The variations in the temperature of animal tissues which accompany variations in function can be measured in the living animal by thermo-electric methods. In these studies the variations in temperature were measured to within 0.01° С.

2. Variations in temperature not only provide a further criterion whereby to identify the organs and tissues which are concerned in the production of vital phenomena, but also suggest the interrelation of the functions of these organs and tissues. 3. The variations in the temperature of the brain under various conditions parallel variations in the histologic picture and in the electric conductivity of the brain under the same conditions. 4. Of particular significance are the findings, (a) that in voluntary muscular activity and as a result of the direct electric stimulation of a nerve the temperature of the brain and of the liver varies in opposite directions; (b) that upon the introduction of hot water

into the stomach the reaction of the brain in increased temperature precedes that of the liver; (c) that the temperature of the liver is but little altered or is unchanged by the injection of adrenalin; of strychnin ; of an acid; of an alkali. 5. The findings in these studies support the conclusions (a) that the brain is the tissue upon which depend the reactions of the organism to stimulation; (b) that the thyroid and the adrenals play essential parts in the production and maintenance of these reactions; (с) that in the performance of its function the brain is indissolubly linked with the liver.

6. The lack of response of the brain to adrenalin in the absence of the liver together with the opposite reactions of the brain and the liver may form vital links in the chain of evidence whereby we may determine the function of each in the electro-chemical operation of the animal mechanism. By б. У. Ске, M.D., AND Ново FRICKE, PH.D. From Proceedings American Philosophical Society, Vol. lxi, No. 3, 1922 The research, part of which is reported in this paper, is a further extension of previous studies undertaken for the purpose of ascertaining to what extent biophysical methods can be used in the investigation and interpretation of medical problems. Our observations of the effect of certain agencies such as adrenalin, anesthetics, stimulants, electrolytes, etc., on the temperature of various organs and tissues of the body have been made with the thought that if the effect of these influences should prove to be uniform and consistent with biological facts, these studies would lead to a wider use of biophysical methods. There are many other studies which will be reported in a later paper in which we expect to set forth an interpretation of our findings. At the present time we wish only to make known the facts which have appeared in these investigations.

Several similar attempts to study temperature changes in the tissues of animals under different conditions have been carried out in the past. In addition to the literature reported in a previous publication, we may especially mention the work of Mosso, who measured the temperature changes by means of a very sensitive mercury thermometer. He believed that he had found that a very great change in the metabolism of the brain followed the injections of certain drugs, among them being absinthe and strychnin. НШ and Nabarro,? however, criticized Mosso's work and made evident that his results were due mainly to the action of the drugs upon the blood circulation.

The amount of oxygen used in the metabolic processes in a state of rest and of excitation is known for many of the body organs in which excitation usually causes a several-fold increased consumption. How the energy corresponding to this oxygen consumption is used, how much is transformed into heat, and how much is used by the organ in the performance of its functions, are questions whose answers have not been directly determined for most organs. In the case of a muscle at work, A. V. Hill? has found that there is a maximum efficiency of fifty per cent. From an estimation of the work done by the organs it is safe to assume that for most organs the major portion of the chemical energy obtained through the oxygen consumption is directly transformed into heat. The chemical energy of the oxygen consumed by an organ under excitation corresponds to a temperature increase of a few tenths of a degree Centigrade per minute. 'The magnitude of this change indicates the feasibility of employing thermocouples for the temperature measurements in the study of metabolic processes.

In the studies reported here’ our attention has been directed especially to the measurement of the temperature changes which occur in the brain. Аз compared with most other organs, the oxygen consumption of the brain is large. It seems probable that the energy corresponding to this consumption is not directly converted into heat for the sole purpose of maintaining the brain temperature, but that it is primarily used by the brain in its special activities, finally appearing as heat in the brain or in other parts of the body. If this is so we would expect that activation of the brain would be accompanied by temperature changes large enough to be recorded.

It is evident, however, that changes in the circulation of the blood, due to vaso-constriction and vaso-dilation in the different parts of the body, must be an important factor in the production of the temperature changes in ап organ. This fact makes the interpretation of the records of temperature change quite complicated. Experimental Technic.—The temperature changes іп the organs studied were measured by means of copper-constantan thermocouples combined with mirror galvanometers. The time of vibration of the galvanometers was about seven seconds. The galvanometer deflections were reflected on a common scale, the resistances in each circuit being so adjusted that a deflection of one division on the scale (equal to two millimeters) corresponded to a temperature change of one one-hundredth of a degree Centigrade. The scale covered a temperature range of 6° C. A specially designed potentiometer made possible the immediate introduction into each thermocouple circuit of an electromotive force corresponding to a temperature difference of 4° C., so that continuous temperature readings could be made over a range of 14° С:

One junction of each thermocouple was inserted in a constant temperature bath, constant to within one one-hundredth of a degree Centigrade, the other junction being inserted in the organ under investigation. In most measurements one thermocouple was inserted in the brain and one in some other organ or tissue. In some cases, however, three thermocouples were employed. In order to avoid the influence of bioelectric, or galvanic forces, it is necessary to insulate thoroughly the wires that are inserted in ап organ. This was done by enameling the wires and coating them with de Khotinsky cement.

A special metal holder was constructed for the thermocouple that was inserted in the brain. The wires, constantan No. 35 and copper, No. 40, were passed through a hard rubber cylinder, the thermojunction extending about one centimeter beyond the end of the rubber, the exposed portion being covered with de Khotinsky cement which served also to cement the thermojunction in place. The skull of the rabbit was trephined to make an opening 6 mm. in diameter and the holder clamped in place, the hard rubber rod with the thermocouple junction being then inserted. The depth of penetration of the brain varied in different experiments from 9 mm. to about 8 mm. The trephined opening was made to the right of the mid-line on a level with the posterior superciliary ridge.

The thermocouples inserted in other organs also were constructed of No. 35 constantan and No. 40 copper wire. The wires were soldered together, the constantan wire extending about three inches beyond the junction. By passing this free end through a needle the junction could be readily drawn into the desired рові- tion within the tissue. We wish to express our appreciation of the codperation of Mr. Seitz of the Electromechanical Engineering Department of the Cleveland Clinie in the construction of the apparatus described above.

. In a later paper we propose to discuss the relative rôles played in these temperature changes by alterations in the blood circulation, in the blood temperature, and in the metabolism of the organ. Inhalation anesthesia.—Ether in its first stages frequently produced an increase in the temperature of the brain. As the depth of the anesthesia was increased the temperature fell. -Nitrous ovid as compared with ether showed a less marked change in the temperature and fewer flunctuations, thus giving a more stabilized curve.

Chloroform showed an TA rise in temperature corresponding to that produced by ether. When full anesthesia was established the temperature fell. Adrenalin: A number of observations have been made of the effect of the intravenous injection of adrenalin upon the temperature of the brain, the liver, the thyroid gland, the adrenal glands, the spleen, the intestines, the kidneys, and the muscles. The uniform dosage employed throughout was the same as that used in previous researches, viz., 0.4 сс. per kg. of 1:1000 adrenalin chlorid (P. D. & Co.).

In every case, the brain showed a very characteristic rise in temperature, the temperature increase continuing for from ten to fifteen minutes and amounting, on an average, to about 0.7° C. The other organs usually showed an effect just opposite to that in the brain, the minimum temperature, however, usually occurring a few minutes later than the corresponding maximum for the brain. In several cases the temperature of the spleen and of the intestine fell markedly, in some cases as much as two degrees or more.

In all the above experiments the thermocouple was inserted in the gray matter of the brain and in every case a rise in temperature was noted. It was found, however, that when the thermocouple was placed in the white matter, no change in temperature occurred after the injection of adrenalin. Amyl Nitrite: The inhalation of amyl nitrite produced a marked rise of 1.1° С, in the brain temperature, the liver showing no decided effect, excepting a slight, continuous decrease in temperature.

Hlectrolytes: The action of sodium and calcium chlorid has an important theoretical interest. Тһе well-known antagonistic relation existing between sodium chlorid and calcium chlorid was strikingly illustrated. The doses given were 2 cc. of a saturated solution—36 per cent—of sodium chlorid and 1 сс. of a 10 per cent solution of calcium chlorid. Sodium Cyanid. The action of a strong poison was shown by various injections of sodium cyanid. The injection of 0.001 № solution caused a slight rise of temperature, corresponding to the stage of excitement. The injection of 0.01 N solution produced a state of depression, while an injection of 0.1 № solution caused an immediate drop in temperature followed by a marked rise during a period in which violent tremors and convulsions were occurring. During these convulsions the temperature fluctuated over a range of 0.1° С. The result of the injection of still stronger doses was an immediate, rapid decrease in the temperature of the brain followed in a few minutes by death. |

1. By means of direct measurements of the variations in the temperature of animal tissues, new light may be thrown upon the action of any agent upon the organism. 2. The observations thus far made are consistent. with the clinieal observations, and with the findings in other forms of physiological research. 3. The opposite effects of the injection of adrenalin upon the brain and upon other organs and tissues demand especial consideration. 4. The use of the biophysical method of measuring variations in function opens the way to further applications of biophysical methods in the study of physiological problems.

From the Journal of Pharmacology and Experimental Therapeutics, Vol. xxi, No. 6, July, 1923. In previous reports of our thermo-electric studies of temperature variations in animal tissue we have noted that the injection of adrenalin in normal animals was uniformly followed by a rise in temperature of about 0.5° C., the periods of rise and fall being practically uniform, and the curve being completed in approximately ten minutes. If further studies should prove that we аге correct in our assumption that variations in the temperature of the brain indicate alterations in its oxidative power, then this response to adrenalin would be an indication of the oxidative power of the brain and it should be possible to compare the effects of various agents upon the oxidative power of the brain by measuring the response of the brain to the injection of adrenalin after the injection or application of those agents. In the following studies theréfore the effects of various drugs upon the temperature of the brain and also of the liver have been observed, the variations in temperature being measured by means of specially constructed thermocouples.

In a previous report * we have stated that the effects of strychnin upon the temperature of the brain vary in relation to the clinical * Read before the Pharmacological Society of the Federation of American Societies for Experimental Biology, Toronto, Ont., December 27-29, 1922. effects. That is, in an animal in which typical convulsions occurred there were correspondingly great variations in the brain temperature while in. another in which the muscular contractions were less marked the variations in the temperature of the brain were correspondingly less than in the former instance. In no instance was the temperature of the liver notably affected.

For the further interpretation of these findings, in view of the conclusions summarized above, 6 animals were given a standard dose of adrenalin (0.4 се. of a 0.001 per cent solution— P. D. & Co.—per kilogram) after the injection of varying doses of strychnin. The resultant effects upon the temperature of the brain and the liver are shown in Table 1. The interesting feature of these observations is the opposite effect of the injection of adrenalin in the presence of strychnin upon the temperature of the brain and of the liver. The rise in the temperature of the brain after the first dose of adrenalin varied from 0.25 to 1.2906; the fall in the temperature of the liver varied from 0.4 to 1.8?C. The marked fall in the temperature of the liver is noteworthy in contradistinction to the lack of effect of strychnin alone upon the temperature of the liver which has been noted above.

In view of the diversity of opinion regarding the influence of morphin on the consumption of oxygen and of the known fact that morphin acts primarily upon the higher centers in the cortical portion of the brain, it seemed of especial importance to study the effect upon the temperature of the brain of the injection of adrenalin in the presence of narcotization by morphin. Five experiments were performed, the results of which are given in Table 2. A study of this table shows that the amount of increase in the temperature of the brain after the injection of adrenalin was in direct relation to the depth of narcosis of the rabbit, varying from 0 and 0.05 to 0.2°C. in deeply narcotized rabbits, and from 0.25°C. in a slightly narcotized rabbit to 0.5?C. in a rabbit in which the morphin produced scarcely any clinical effects. The effect of adrenalin upon the temperature of the liver was in the opposite direction to that upon the temperature of the brain and in general this effect also was in direct relation to the depth of the narcosis. In 4 cases no response was noted in the liver temperature; but in one very strongly narcotized rabbit a very marked fall in temperature was noted after each of 2 injections of adrenalin—of 0.8 and 0.65°С., respectively.

In 6 experiments 15 се. of а 20 ‘рег cent solution of sodium bromid was injected intravenously on each of three consecutive days. At varying periods after the injection on the third day a standard dose of adrenalin was injected. No variation from the normal response to adrenalin was observed. There was no notable effect upon the temperature of the liver. It appeared that it might be of interest to establish the temperature variation in the brain in the absence of any metabolie activity in the voluntary muscular system. Since curare acts specifically. on the neuro-muscular plates its injection. would cut down. the metabolism of the muscular system. as a whole. In 2 animals therefore 10 mgm..of a 0.5 per cent solution of curare was injected intramuscularly. Artificial respiration was established and the usual injection of adrenalin was given. The only alteration in the response of the brain was that the temperature rise was somewhat delayed and was less than the normal average response but not less than the response observed in some normal animals. ‘There was no effect upon the temperature of the liver.

‚ Since atropin produces an increased blood pressure as the result of the contraction of the arteries of the splanchnic area and to some extent produces peripheral vasodilation, it would appear that in all probability the blood supply to the brain would be increased by the injection of atropin. If the increased temperature of the brain which follows the injection of adrenalin in normal animals is due to an increased blood supply to the brain then it would follow that the injection of adrenalin after the injection of atropin would produce a greater rise in the temperature of the brain than that observed in normal animals. "Three experiments were performed in which no variation from the normal response was noted, the rise in temperature in the 3 rabbits utilized being respectively 0.6, 0.45 and 0.4°C. In contradistinction to other experiments, however, a gradual rise in the temperature of the liver of between 0.3 and 0.4°C, was noted.

(osuodsei ou ` Kqpeoroeid әлед әлләи |влошој jo Suryouid) doop Алол :тү esoq шдоиәмрто fo wowootwv 291 1010 sabunyo олтарлофшој fq ројроурша sp soar 241 рир шилд 291 fo лото эамтршо əy} uodn mydiou fo эээ эчү, Since caffein stimulates especially the cortical centers of the brain, it was suggested that it might be of value to note its effect upon the temperature of the brain. Two experiments were performed in which each rabbit was given 2 subcutaneous doses of caffein, of 0.5 grain each ten minutes apart. The subsequent injection of adrenalin was followed by a rise in temperature which did not vary in amount from that observed in normal animals but did vary from the normal response in its abruptness. That is, the rise began while the injection of adrenalin was being given and the temperature rose to the maximum point with extreme rapidity. No notable change in the temperature of the liver was observed.