Fred R. Griffith

Vasomotor Control of the Liver Circulation

Our present knowledge of the vasomotor control of the liver circulation is curiously inadequate. In due time the evidence for this conclusion will be reviewed in detail; now we wish merely to record a summary of the results which have been obtained during the last couple of years in a study of this problem, using cats under chloralose anesthesia and the liver plethysmograph previously referred to. 1 , 2 The peripheral vagus has no effect on liver volume; we have stimulated it in the neck (after denervating the heart according to Cannons method), below the heart in the thorax and after emerging through the diaphragm. The postganglionic fibers of the hepatic plexus constrict not only the terminals of the hepatic artery but also those of the portal vein. The preganglionic fibers of the splanchnic (left) have exactly the same effect on liver volume, either by way of the artery or portal vein, as stimulation of the postganglionic fibers in the hepatic plexus. Reflex pressor responses are accompanied by decreased liver volume; depressor reflexes produce dilation in the liver. If, however, the liver is denervated by cutting the fibers of the hepatic plexus, its volume then follows passively the general blood pressure. During the generalized vasomotor activity induced by asphyxia (rebreathing the air in a small balloon) the liver constricts powerfully during the rise of general blood pressure and remains constricted even as the heart begins to fail. If it is denervated, however, it dilates for a time as the general blood pressure is rising; but before this has reached its maximum the liver often begins to constrict maximally. This delayed constriction may be prevented by removal of the adrenals; then the denervated liver volume passively follows the general blood pressure throughout the course of the asphyxia.

Effect of Adrenalin and Pituitrin on the Volume of the Liver.

In view of the contradiction which exists in the literature in regard to the effects of adrenalin and pituitrin on the circulation in the liver, we have used the liver plethysmograph, which has been previously described, 1 in a new attack on this problem. The results will be very briefly described in this preliminary report without substantiation from actual records or attempt to cite the literature; these will appear in due time. Cats and rabbits under chloralose anesthesia have been used in this work; the results are as follows: I. Intravenous injections of adrenalin. 1. Pressor doses invariably produce constriction in the liver, whether introduced by way of the femoral, or portal veins, or hepatic artery, provided the general blood pressure is high and the animal in good condition. This constriction may last as long as the pressor response or it may at times give way to prompt and active dilation; when this latter occurs it may be abolished by section of the depressor nerves (rabbit). On the other hand, if the animal is in poor condition with low blood pressure the liver apparently dilates passively during the pressor response to an injection by way of the femoral vein. This is intensified by first clamping the hepatic artery, but is prevented altogether and even replaced by constriction if the portal vein has been previously clamped so as to restrict the volume changes in the liver to variations in its arterial blood supply; i. e., the liver is forced to expand under these conditions and in spite of active vasoconstriction within itself, because of an engorgement through its massive portal supply. This in turn is probably due to an unusual movement of blood through the toneless (?) mesenteric capillaries as a result of the high general blood pressure.

Changes in the blood sugar and blood gases during exercise.

It has been found by Scott and Hastings 1 that exercise causes a slight decrease in blood sugar and an increase in the oxygen content of the blood of dogs when they are made to work on an electrically driven horizontal treadmill at the rate of five miles an hour. We have made a study of the influence of exercise on the blood sugar and blood gases of several cats and one dog. The animals were exercised in a circular treadmill with a tread 5.75 meters long. Blood was collected under paraffin oil from an incision in an ear vein. The gases were analyzed immediately by Van Slykes method of determining 2 the oxygen and carbon dioxide in one cubic centimeter of blood. Sugar was determined by the method of Hagedorn and Jensen. 3 Ten cats were studied in which the blood sugar alone was determined. With five other cats and the dog the sugar, oxygen and carbon dioxide of the blood were determined. In the latter set, two or three experiments were performed with each animal. In all but one case the cats were exercised by driving the treadmill by hand. The animals usually worked from ten to thirty minutes travelling from 500 to 1500 meters. In every instance where this was done, the blood sugar invariably increased more than 100 per cent, occasionally as much as 400 per cent. In these ex-periments the carbon dioxide was lowered markedly, commonly to twelve volumes per cent and occasionally as low as eight volumes per cent. This was apparently caused by the very rapid breathing accompanying the strenuous exercise. The oxygen was at first increased and then later decreased in some experiments.

Use of Illuminating Gas to Check Metabolism Apparatus

Combustion of alcohol, ether or acetone is standard procedure to check the operation of metabolism apparatus (Carpenter, et al. 1 ). We have found it impossible, however, to devise a burner by which the combustion of any of these would proceed evenly for meta-bolically significant periods at rates comparable to the respiratory metabolism of the rat. On the other hand, small validity would seem to attach to a test several times more severe than planned capacity; failure would be no indication of inability of the apparatus to do what it was designed to do; nor would success be any guarantee that it could perform the more delicate task for which it was made. A micro-balance is not checked with kilogram weights. As a result, recourse has been had to combustion of gas which can be successfully controlled at almost any desired rate. It was originally intended to use a pure, commercial preparation of one of the lower hydrocarbons in order to eliminate the necessity of control determinations. Preliminary work with ordinary illuminating gas from the city mains was so satisfactory, however, that it has been adhered to; especially since equipment was at hand for the necessary control determinations which involve only slightly additional work. Since the only difficulty in the application of this principle is accurate measurement of the small volume of gas burned, description of an apparatus which has been found accurate and simple to operate and is easily assembled from odds and ends about any laboratory may be of interest. This apparatus is shown diagrammatically in Fig. 1. The gas sample. Since the composition of the city gas supply is not absolutely constant, gas is not burned directly from the supply line. Instead, a sufficient sample for several runs and their attendant control determinations is secured in the 18 liter carboy (C1) by water displacement into the similar carboy (C).

Action of Adrenalin on the Metabolism of Peripheral Tissues.

It has been found impossible to affect the carbon dioxide or total acid production of excised frog muscles by placing them in adrenalin solutions. 1 The absence of a calorigenic effect 2 under such unphysiological conditions was not surprising; and more recent work has indicated that the absence of the viscera 3 and particularly of the liver 4 may have been as responsible for the negative result as the lack of proper circulation or other abnormal conditions to which the muscles themselves were immediately exposed. It is not known in what manner the viscera cooperate in the calorigenic action of adrenalin; whether by serving as the locus of its action, or by keeping the peripheral tissues in the proper physiological condition to respond to the adrenalin itself. The following experiments were undertaken to determine some of the effects that might be produced in one of the hind legs of an anesthetized cat upon the addition of a known amount of adrenalin, directly to its arterial blood supply. All experiments were done on cats under chloralose anesthesia. The animal was always prepared so that simultaneous samples could be taken of the arterial blood going to and venous blood coming from the left hind leg. At the time of collection of the venous sample the rate of flow was also determined in a manner somewhat similar to that described by Himwich and Castle. 5 The usual precautions were taken to prevent alteration in the gas content of the blood; and this was determined by the manometric method of Van Slyke and Neill, using 0.2 cc. samples in duplicate. In large cats that could stand the additional loss of blood, 2 normal sets of samples, 10 or 15 minutes apart, were taken before the adrenalin injection; these served to establish the average spontaneous variation to be expected under the conditions of these experiments. In the remaining experiments the adrenalin was injected immediately after taking a single normal pair of samples.

Carbohydrate mobilization in body temperature regulation.

This is to report the effect on the blood sugar level of cats of a “heat liability,” produced by giving ice water by stomach tube, according to the method devised by Cannon. Eight animals have been used and all have given concordant results, of which those for one cat shown in the figure are typical. From inspection of the curves (and deducting the effect of the similar procedure in which water at body temperature was given), it appears that such a heat liability induces a pronounced mobilization of carbohydrates and increase of blood sugar value. In spite of the fact that the fall in body temperature is immediate, this mobilization of sugar seems to get under way slowly and is only noticeable after an hour or more. From then on it rises slowly to a maximum during the next hour or two and then, even more slowly, falls; in only two cases out of the eight did the blood sugar value return to normal within the five or six hours during which the animals were kept under observation.

Seasonal periodicity in man: I. Basal metabolism; respiration; cardio vascular condition.:

Four normal persons, two men and two women, have served as subjects for this investiagtion. On each, the following observations were made once a week throughout the year (February, 1925—February, 1926) under basal conditions between 8 and 10 a. m. The observations and their apparent course throughout the year follow: 1. Oral temperature; no certain periodicity. 2. Reclining systolic pressure: all show a marked depression in the spring and in three cases there are also low points in midsummer and late fall—early winter. 3. Reclining pulse: lowest in summer. 4. Alveolar air: (1) Oxygen, uncertain, with perhaps a tendency to be lowest in summer; (2) Carbon dioxid, highest in the summer in all subjects and rhythmically coincident with the menstrual cycle in the women, the low points coming just before the onset of menstruation. 5. Pulmonary ventilation: both the tidal and minute volumes show a marked depression in the spring with a rise to maximum in late summer and early fall. 6. Expired air: the percentages of oxygen and carblon dioxid vary inversly, the former showing a marked low point in spring and a maximum between July and September, while the latter is highest in the spring and lowest during late summer and early fall. 7. Carbon dioxifd per minute: nlo evident periodicity. 8. Oxygen per minute and calories per square meter per hour: lowest in the period, July to September. 9. Respiraltory Quotient non-protein) : with one exception seems to be highest in the summer and early fall. Under the same basal conditions and either just preceding or following the above determinations 20 cc. of blood were taken from an arm vein.

Similarity of effect of adrenalin, adrenaline and nor-adrenaline on the cat denervated heart.

Summary No difference can be seen in the quantitative responses of the acutely surgically denervated heart of the cat to “Adrenalin,” adrenaline or nor-adrenaline. The authors wish to thank the Sterling-Winthrop Research Institute for the supply of 1-adrenaline and Winthrop-Stearns Inc. for the 1-nor-adrenaline used in this investigation.

Effect of Exercise and the Specific Dynamic Action of Fat in Obese Subjects.

The effect of a meal containing 100 gm. of butter and 50 gm. of olive oil mayonnaise, alone, and with exercise, has been determined in 2 normal and 4 non-diabetic obese subjects. The metabolism was determined by collection and analysis of the expired air; after determining the basal metabolic rate the subjects were usually exercised while still in the post-absorptive state and before the ingestion of the fat meal; this gave the post-absorptive metabolism both at rest and in exercise. They were then given the 150 gm. of fat and the resting and exercise metabolism was determined, usually once an hour for 7 to 8 hours. The exercise consisted of having the subject lift the lower extremities, while lying on the back and connected with the spirometer, rhythmically and alternately so as to touch with the toes a board placed a given distance above the foot of the bed. The rhythm was maintained by the use of a metronome which was usually set at about 76 beats per minute, so that a lower extremity was lifted 19 times per minute. This exercise increased the metabolism from 2 to 3 times. The subjects exercised for 2 minutes before collection of the expired air was begun; and this was continued for 5 or 6 minutes, depending on the degree of fatigue produced. In 2 normal subjects and one of the obese there was a slight initial rise in the resting respiratory quotient following the ingestion of the fat; this was followed by a gradual fall, which, at the end of 6 to 7 hours reached a level lower than the resting quotient. In 3 of the 4 obese subjects there was a rise in the resting quotient following the fat meal.

The effect of potassium on the metabolism of surviving muscle tissue.

The following experiments were undertaken in order to determine whether the pronounced effect of potassium on the contractile process in skeletal and cardiac muscle is associated with changes of metabolism, as indicated by variations in the rate of acid production. Isolated frog tissues were used in all the experiments and their “normal” rate of acid production was determined in Ringers solution before treating them with potassium. The Ringers solution consisted of a mixture of the three chlorides, in the usual concentration for cold-blooded tissues, and the potassium effect was obtained by immersing the muscle in an isotonic solution of potassium chloride. Precaution was taken to have the Ringers and potassium chloride solutions of the same pH and buffer capacity. The experiments were carried out at various room temperatures, but never did the temperature vary significantly during any one experiment. The experiments fall into three classes, as follows: 1. The effect of potassium on the total acid production of skeletal muscle. Sartorius muscles were used in these experiments and their rate of total acid production was measured by the indicator method of Haas, 1 using phenol red as indicator. Determinations were made of the time, in seconds, required by a muscle to produce sufficient acid to cause an increase in the acidity of the solution it was in from pH 7.381 to pH 7.168. Each determination was made with the muscle immersed in 2.5 cc. of solution (Ringer or KC1) in a hard-glass test tube of 3 cc. capacity, stoppered with a paraffined cork. At least two determinations were made of the rate of acid production in Ringer solution, in order to establish the “normal”, before treating the muscle with potassium; it was then immersed, without any delay, in isotonic potassium chloride solution, previously adjusted to the same pH and buffer capacity as the Ringer.