Don R. Joseph

A demonstration of the inhibitory effect of magnesium upon normal and artificial peristalsis of the stomach and duodenum

Some years ago J. B. MacCallum 1 made the statement that purgation can be brought about by subcutaneous or intravenous injection of magnesium sulphate. He ascribed the effect to the stimulation of nerve and muscle tissue of the intestines by this salt, which thereby caused increased peristalsis. In a paper by Meltzer and Auer 2 it was stated, however, that magnesium salts not only do not cause peristalsis, but directly inhibit it when normally present or even when aggravated by barium or physostigmin. In opposition to this statement it was asserted in a paper by S. A. Matthews and D. E. Jackson 3 that after injection of magnesium sulphate the peristalsis shows no especial departure from the normal and barium and physostigmin show their usual action.

Simultaneous graphic registration of gastric and duodenal peristalsis in rabbits; a demonstration

The graphic registration of gastric or intestinal peristalsis is usually obtained from an animal with an opened abdomen while in a saline bath and more or less under the influence of an anesthetic. This method hardly reproduces the normal condition as the act of laparotomy reduces and modifies greatly the peristalsis. In some instances the movements of the stomach have been studied from a gastric or œsophageal fistula and in the rabbit the movements can be studied graphically, as it has been discovered by Auer, in the perfectly normal and unanesthetized animal. In the April meeting of last year we presented some tracings showing the effect of magnesium upon gastric and duodenal peristalsis. At the present time we wish to explain more fully the method we have used and to demonstrate the act of obtaining the peristaltic tracing. This rabbit was operated four days ago. The movements of the stomach and of the duodenum are transmitted to the kymograph by means of catheters which carry at one end small balloons of thin rubber. The balloon end of one catheter is introduced and secured in the pyloric part of the stomach and that of the other in the descending part of the duodenum through openings made directly in each of these parts.

A demonstration of the life-saving action of eserin in poisoning by magnesium

At the May meeting of this Society, one of us (J.) reported that by the use of magnesium, certain toxic effects of physostigmin can be completely overcome. In our present communication we wish to bring out the fact that the antagonism between physostigmin and magnesium is mutual, at least to a certain extent. We wish to show an experiment which demonstrates that physostigmin can overcome certain toxic effects of magnesium and thus save the life of a poisoned animal. Both these rabbits (A and B) received at about the same time 1.2 gram of magnesium sulphate per kilo of body weight. The injections were given intramuscularly in the lumbar region. Rabbit B received in addition one milligram of eserin, also intramuscularly. Rabbit A is already dead. Rabbit B is still alive; although anesthetic and limp, it breathes regularly and apparently is in no danger of death. 1

The effect of adrenalin on the pupil after removal of the ciliary ganglion

Cats were used exclusively in these experiments. One ciliary ganglion was removed under ether anesthesia. The comparative irritability of the two irises to minimal doses of adrenalin was tested soon after the operation (1 to 4 hours) and again later (22 to 55 or more hours). In a few cases tests were made as long as 60 to 77 days after the operation. The adrenalin was injected into a saphenous vein. No ether was required. Stated briefly the results are these: Removal of the ciliary ganglion renders the corresponding iris hypersensitive to adrenalin. Some increase in sensitiveness is occasionally seen within an hour after removal of the ciliary ganglion, but in most cases the maximal increase does not appear under 4 hours. The heightened irritability to adrenalin was still present after 60 to 77 days. The irritability of the gangliectomized iris was from 3 to 20 times as great as that of the normal iris. The adrenalin effect lasted definitely longer in the operated eye than in the normal. After the smallest doses used this difference was not great, but after the larger doses (e. g., 1/50 c.c. 1 : 1,000 Parke Davis solution) it was marked—for example, the normal iris recovered completely within 10 to 20 seconds, while the iris deprived of its ciliary ganglion required from 3 to 4 minutes for recovery. Adrenalin produces, after removal of the ciliary ganglion, a dilatation of the pupil.

A quantitative study of the pupil dilatation caused by adrenalin

In the normal rabbit, adrenalin given subcutaneously has no effect on the pupil; if given intravenously in fairly large doses there may be a dilatation lasting less than a minute. S. J. Meltzer and C. M. Auer have shown that after removal of a superior cervical sympathetic ganglion in rabbits, the pupil of the corresponding side dilates maximally upon the administration of adrenalin either subcutaneously, intravenously or by instillation. Their experiments were carried out from the qualitative point of view, that is, fairly large doses of adrenalin were used and a wide, long-lasting dilatation of the pupil on the gangliectomized side resulted. I have recently made a quantitative study of the effects of intravenous injections of adrenalin on the pupil after removal of a superior cervical ganglion in rabbits. The object was to determine the minimal dose that will give a dilatation, and also the amount and duration of the dilatation produced by larger doses. The doses of adrenalin used per kilo animal, expressed in c.c. of the 1/1,000 commercial adrenalin solution, were 1/50, 1/30, 1/20, 1/10 and 2/10 c.c. The results, stated briefly, are as follows: The average pupildilatation in six experiments with 1/50 C.C. of adrenalin per kilo animal was 1.62 mm., with a beginning recovery from dilatation in four minutes, and a complete recovery in ten minutes. In six experiments with 1/30 C.C. there was an average dilatation of 2.25 mm.; recovery began in eight minutes and was complete in twenty-eight minutes. In thirteen experiments with 1/20 c.c., there was an average dilatation of 3.61 mm.; recovery began in six minutes and was complete in thirty-seven minutes. In eight experiments with 1/10 c.c., there was an average dilatation of 3.87 mm.; recovery began in ten minutes and was complete in forty-nine minutes.

The inhibitory effect of magnesium upon indirect and direct irritability of frog muscle and the antagonistic action of sodium and calcium upon this effect

Several series of experiments were carried out on frogs. In the first series magnesium chloride was injected into a lymph sac and subsequently nerve and muscle were stimulated at various times by induction shocks. Of the results obtained two will be mentioned: One is that indirect irritability gradually disappeared completely while direct irritability remained practically unchanged, that is, on stimulation of the nerve plexus there was no response while on stimulating the muscle directly there was a good contraction. Such a result was seen by many observers and was spoken of as curare-like action. In a previous paper we have called attention to the fact that similar results can be obtained also by perfusion of the leg with solutions of sodium chloride and even with calcium chloride. The magnesium effect, however, is somewhat more pronounced. The second result is that the subsequent infusion of the muscles through the abdominal aorta, with calcium chloride, restores rapidly the abolished indirect irritability. This is similar to the observation of Auer and Meltzer on the antagonistic action of calcium to magnesium in mammals and is also similar to the antagonistic action of calcium to the curare-like action of sodium chloride.

The origin of convulsions and paralysis following the intravenous injections of the hypertonic solution of sodium chloride

In our experiments on the comparative toxicity of chlorides in which, among others, we studied the effects of intravenous injections of a molecular solution of sodium chloride in dogs we observed that after a certain quantity of the solution runs in, twitchings of the muscles of the entire body begin which gradually develop into more or less strong convulsions. Later these gradually grow weaker and finally subside completely, at which time also the respiration stops. The heart continues to beat for several minutes longer. This chain of events is ascribed by pharmacologists to the osmotic action of the hypertonic solution and is generally termed salt action. Loeb however demonstrated that sodium chloride exerts on the living tissue a chemical action also. In the paper embodying the above mentioned experiments we made the following two suggestions: (1) that the twitchings and convulsions are perhaps comparable to the twitching of frog muscles which develop when they are immersed in solutions of sodium chloride; the convulsive movements would be then of peripheral origin; (2) that the subsidence of the convulsions and the paralysis might be due to the curare-like action of the sodium chloride, i. e., to the paralysis of the motor nerve endings.

The mutual antagonistic life-saving action of barium and magnesium. A demonstration

For rabbits, 1.2 grams of magnesium sulphate per kilo body-weight are invariably fatal in intramuscular injection; they usually die in less than twenty minutes. The rabbit to the right (A) received such a dose and has been dead for some time. The rabbit in the middle (B) received a similar dose of magnesium and is still alive; it breathes regularly. This animal received also an intravenous injection of barium chloride, which is the cause of its surviving the fatal dose of magnesium. By a special study we are enabled to state the mode of the antagonistic action of the barium which is this: the fatal action of magnesium is due to a paralysis of respiration and barium counteracts just this effect of magnesium. It differs from the antagonistic action of calcium inasmuch as calcium antagonizes all the effects of magnesium, while barium picks out only the respiration, the animal remaining anesthetized and paralyzed.

The influence of sodium and calcium upon direct and indirect muscle irritability and their mutual antagonistic actions

By the researches of Kühne, Biedermann, Ringer, Loeb, and many others, it is established that solutions of sodium chloride cause rhythmical movements of the muscles of the frog, and that the addition of a small quantity of calcium will stop them. By the researches of Locke, Carslaw, Cushing, Poljakoff and Overton, it is further established that solutions of sodium chloride abolish indirect irritability, and that the addition of a small dose of calcium restores it. There has been very little work done on the primary effect of calcium upon the direct and indirect irritability of the skeletal muscles of the frog and there are practically no researches on the action of sodium upon the primary effects of calcium. In our experiments, sodium and calcium chlorides were employed in M/10 solutions and were introduced by infusion through the abdominal aorta according to the method described by Cushing. 1 The graphic records were obtained from the gastrocnemius and the sciatic plexus was stimulated at about one minute intervals by two consecutive shocks (make and break) from an induction current.

The relative toxicity of the chlorides of magnesium, calcium, potassium and sodium

Sodium, potassium, calcium and magnesium are normal constituents of the animal body. However, when introduced intravenously in larger quantities they may have a poisonous effect. Pharmacologists frequently speak of the effect as a salt action. This means, at least according to the definition of some pharmacological writers, that the effect is due to osmotic changes. If this were true, the toxicity of all four inorganic, basic elements ought to be the same if introduced in the same molecular concentration. Although, as far as we know, a direct comparative study of the toxicity of these inorganic substances has never yet been made, a glance at the various data in the literature suffices to show that these substances differ greatly in their toxicity. As far as we can gather, it is generally assumed that potassium is the most poisonous; calcium seems to be considered a good deal less poisonous than potassium, but definitely more so than magnesium. As to sodium, only recently Loeb and his pupils called attention to its poisonous effect. In a series of experiments on dogs, we compared the toxicity of these four inorganic elements in intravenous injections of their chlorides. In every instance molecular solutions were employed. The toxicity of each of these salts was tested on twelve animals. The injections were made by four different methods, using three dogs for each method, namely, by injections through the jugular vein, through the femoral vein, through the splenic vein, and intra-arterially, through the central end of the carotid artery. In the latter case the solution was driven by high pressure through a capillary tube. Except in the case of sodium chloride, the solutions ran in uniformly one C.C. per minute.