Experimental studies of the influence of cortisone upon the cardiac action of digitoxin
[영문]A similarity in the chemical structure of the adrenocortical hormones and of digitalis aglycones has attracted the attention of many investigators. There have been extensive studies made of the action of the corticosteroids on cardiac function. In animals treated for ten days with desoxycorticosterone Lown(1951)
noted an increased in susceptibility to the cardiotonkc action of digitalis. In studies of the effects of adrenocortical hormones on the heart, as measured by changes in the electrocardiogram, Da Vanzo(1961) and Bruchell et al.(1953) observed inversion of the T-wave after administration of mineralocorticoids, and diphasic
T-waves after glucocorticoids were given. On the contrary, Roberts(1953) found no significant changes in the electrocardiograms made after the administration of
cortisone. Small doses of Compounds B, F, E. and S exert cardiotonic action k but the cardio-inhibitory action of desoxycorticosterone is independent of the dosage used(Emele and Bonnycastle, 1956). In studies on the isolated cat's heart
Tanz(1960) noted that cortisone, in small doses, caused cardiac stimulation, but in large doses caused cardiac inhibition.
In addition to these reports there is a voluminous literature on the relationship between the adrenocortical hormones and digitalis glycosides. Corticosteroids significantly influence potassium balance and the cardiac effects of digitalis vary
according to the concentration of potassium in the cardiac muscle.
Because of the recent marked increase in the frequency of the administration of cortisone there is an increasing possibility for a cardiac patient, particularly one who is already receiving digitalis glycosides, to receive cortisone. In such a patient cardiac function would be influenced by cortisone. These facts have initiated the author's interest in a study of the influence of cortisone on the cardiac effects of digitoxin.
A. The influence of cortisone on the action of digitoxin on isolatd heart preparations.
1. The experiment on the isolated auricles of the cat.
The cat's heart was rapidly removed under ether anesthesia, and, after separation of the auricles fro the ventricles, connective tissue, fat, and blood vessels, the auricles were suspended in a glass muscle chamber containing Tyrode's solution
maintained at 38℃. Oxygen was constantly bubbled through the bathing solution. Amplitude of muscle contraction was recorded on a kymograph using an isotonic lever. Changes in the contractile amplitude and rate of spontaneous contraction were determined before and after the administration of selected drugs. Digitoxin in doses of 1:1 million caused a progressive increase in the amplitude of cardiac muscle contraction until the onset of arrhythmia. Then there was a relatively rapid decrease in the amplitude of the contraction to a final arrest of the heart beat.
In six experiments the average time between the administration of digitoxin and the appearance of the arrhythmia was 16minutes(13-21 minutes). The time from drug administration to muscle arrest averaged 24 minutes(21-34 minutes).
In studies of the influence of cortisone the hormone was administered for an hour following which digitoxin was given to the auricles. In preliminary experiments it was found that cortisone, 1:200,000, produced only an immediate and transient
slight decrease in the amplitude of contraction. However, when digitoxin 1:1 million was given to the auricles, after the administration of cortisone 1:200,000 as above, arrhythmia appeared in an average of 6 minutes(4-11), and muscle arrest
occurred in an average of 14 minutes(9-26) out of seven experiments. These findings indicate that, in the isolated auricles of the cat, digitoxin toxicity is increased when given with cortisone.
2. The experiment on the isolated papillary muscle of the cat.
According to the procedure described by Cattell and Gold one or two of the ventricular papillary muscles were isolated in a muscle chamber which contained 100ml of Tyrode's solution at 38℃ through which oxygen bubbled constantly. A square wave stimulator stimulated the muscle continuously at a rate of one impulse
per second lasting for one millisecond at a supra-maximal voltage. After the contraction amplitude for the muscle was constant the test drugs were added to the water bath. Following the administration of digitoxin 1: 500,000 there was an increase in the amplitude of the muscular contraction for a period of time, but then there was a relatively slowly decreasing contraction amplitude, and eventually cessation of the muscle contraction. In only one of the five experiments was there
any arrhythmia and it was transient. The arrest of muscle contraction came at an average of 46 minutes(31-60) after digitoxin was placed on the normal papillary muscles of the cat. In preliminary experiment, it was found that cortisone
1:200,000 produced no significant action on the papillary muscle of the cat. the administration of digitoxin 1:500,000 on the papillary muscle pretreated with cortisone 1: 200,000 for an hour, caused cardiac arrest in an average of 63 minutes out of 6 experiments.
This results indicate that cortisone has no effects on the cardiac activities of digitoxin on the papillary muscle of the cat.
3. The experiment on the heart-lung preparation of dog.
In a Patterson and Starling heart-lung preparation, as modified by Krayer and Mendez, right atrial pressure was continuously recorded using a water manometer. Also the changes in arterial pressure, in heart rate, in systemic cardiac output and in the electrocardiogram were recorded after the administration of drugs, and compared with the levels noted before any drugs were given.
After the addition of 3mg of digitoxin to the 300ml of blood in the blood reservoir the following changes were noted: a prolongation of the P·R interval, a shortening of the Q-T interval, the onset of an A-V block with premature ventricular beats, ventricular tachycarida, fibrillation and ultimately cessation of the heart beat.
When the heart-lung preparation was given cortisone for an hour previous to the administration of digitoxin there was a significant intensification of the above cardiac changes. In the former animal the heart beat stopped at an average of 45 minutes after the administration of digitoxin, but in the animals pretreated with cortisone, cardiac arrest came about 25 minutes after the administration of digitoxin. This is a difference which is statistically significant. The cardiac toxic effects of digitoxin on the heart-lung preparation from dogs which received
cortisone 2mg/kg daily for two weeks were found to similar to those observed in the heart-lung preparation pretreated with cortisone for an hour prior to the administration of digitoxin. In conclusion, cortisone increases the cardiotoxic effect of digitoxin in the heart-lung canine preparation.
B. Studies of the influence of cortisone in dogs which have been given toxic doses of digitoxin to cause acute intoxication.
Dogs were given pentobarbital sodium anesthesia(30 mg/kg). A mercury manometer inserted into the femoral artery constantly recorded the blood pressure on a kymograph. Also electrocardiographic changes were noted while digitoxin was being
infused into the femoral vein through a constant-rate infusion apparatus.
In normal dogs the continuous infusion of digitoxin at 0.0056mg/kg/min was followed by marked prolongation of the P-R interval, the onset of ventricular tachycardia, and cessation of heart beat 94 minutes(72-155), 103 minutes(81-158) and 133 minutes(177-64) after the drug administration was started. The average lethal dose of digitoxin is 0.75mg(0.66-0.92) of digitoxin per kilogram of canine body weight.
In studies of the effect of cortisone on digitoxin toxicity the same amount of digitoxin(0.0056mg/kg/min) was continuously infused into the femoral vein of dogs which had been prepared with cortisone given in doses of 2mg/kg/day for three weeks. The following electrocardiographi changes were noted: a marked prolongation of the P-R interval, the onset of ventricular tachycardia, cessation of the heart beat appeared in an average of 60minutes(45-70), 71 minutes(48-88) and 97 minutes(64-123).
The average lethal dose of digitoxin was 0.54mg(0.36-0.69) per kilogram of canine body weight. This is significantly lower than that observed in the normal dogs(0.75mg)(P<0.05).
C. Studies of the influence of cortisone in dogs which are chronically intoxicated with digitoxin.
Four groups of dogs were used in this study: first, a control group which received no drugs; second, a group receiving digitoxin 0.5mg/kg, in daily intravenous injections; third, a group receiving cortisone in 2mg/kg daily intramuscular doses; and lastly, a group receiving both drugs-digitoxin in doses of
0.5mg/kg, and cortisone in doses of 2mg/kg/peer day. Over a period of 4 to 5 weeks electrocardiographic studies sere made on all dogs and changes carefully observed.
In the control and in the cortisone-treated group there were no significant changes noted in the electrocardiographic studies. In four dogs which had been given digitoxin there was a marked prolongation of the P·R interval which change was noted on the 18th day(15-19). However in the group which had received both
digitoxin and cortisone, the marked prolongation of the P-R interval appeared on the 9th day.(5-12). This is significantly sooner than the changes noted in the group which did not receive cortisone. These findings indicate that cortisone may enhance the action of digitoxin on the transmission of the cardiac impulse from the auricle to the ventricle.
In conclusion: The studies indicate that cortisone itself does not produce any significant effects upon the heart, but that it does enhance the cardiotoxic effects of digitoxin. the mechanism of this action has been discussed.