Adrenocortical Steroids가 Digitoxin 심장독작용을 증강시키는 기전에 관한 실험적 연구

Abstract

[한글]

Experimental Studies on the Enhancement of Cardiac Toxicity of Digitoxin by

Adrencortical Steriods

Hyun Soo Whang

Department of Pharmacology and Toxicology

Yonsei University, College of Medicine, Seoul Korea

(Directed by Prof. Woo Choo Lee)

Because of the similarity in the chemical structures of adrenocortical steroids

and of digitalis aglycones, extensive studies have been reported concerning the

cardiac activities of the cortical steroids. However, none of these steriods have

been shown to be a cardiostimulant as potent as digitalis glycosides. In the

studies of the cardiac action of cortisone, Lee(1963) fround that cortisone itself

does not produce any significant effects upon the heart, but that it does enhance

the cardiotoxic activity of digitoxin. Lown et al (1951) also reported that the

animals treated with desoxycorticosterone for ten days showed a marked increase in

susceptibility to the cardiotonic action of digitalis. In view of the recent

increase in the frequency of the administration of cortical steroids, there is an

increasing possibility for a cardiac patient, particularly one who is receiving

digitalis glycosides, to receive these steriods. In such a patient, unexpected

cardiac toxic manifestation may be produced by these drugs. Therefore, it seems to

be worthwhile to study the mechanism by which cortical steroids potentiated to the

cardiac toxicity of dgitalis glycosides.

It has long been known that adrenocortical steroids, particularly,

desoxycorticosterone and aldosterone promote the urinary excretion of potassium

resulting in a decrease in intracellular potassium content. On the other hand,

although conflicting evidence has been presented in regard to the effects of

digitalis on the potassium content, numerous investigators have found a diminished

potassium in the myocardium after the administration of digitalis in toxic doses.

It is, therfore, reasonable to expect that potassium depletion would be an

important factor in the mechanism by which cortical steroids potentiate the cardiac

toxicity of digitalis.

In an attempt to elucidate the mechanism of potentiating effects on the

cardiotoxic activity of digitoxin by cortisone, the present experiment was

undertaken to obtain evidence with regards to the effect of these drugs on the

myocardial potassium content.

Healthy mongrel dogs weighing approximately 10kg were ?mployed in this

experiment. Under pentobarbital sodium (30mg/kg) anesthesia, tracheotomy was made

for artificial respiration. Arterial blood pressure was contincously recorded on a

smoked kymograph through a mercury manometer connected the left femoral artery.

Polyethylene tubes were inserted into the right femoral artery and vein

respectively and a single lumen catheter, filled with heparin was placed via the

external juglar vein in the coronary sinus to obtain blood samples. Heparin

(5mg/kg) was administered to prevent clotting of blood. Digitoxin was delivered

into the left femoral vien by a constant infusion pump at a rate of 0.2mg/kg/min

until cardiac arrest ensued. Frequent electrocardiographic changes were recorded

during the experiment. The coronary arterio-venous (A-V) difference of sodium and

potassium were determined as a measure of their net uptake by, or release from, the

myocardium. After the deathe of animals, auricular and skeletal muscles were

analyzed for sodium and potassium. The Patwin Flame Photometer was used for

measuring potassium and sodium in the plasma and muscle.

The experimental animals were divided, at random, into the following three

groups.

Group 1: 9 normal dogs.

Group 2: 5 dogs treated with cortisone acetate 2.0mg/kg intramusculary daily for

14 days.

Group 3: 5 dogs treated with desoxycorticosterone in a daily dose of 25mg for

from 7 to 14 days.

Results and Discussion

1. In normal dogs the continuous infusion of digitoxin produced a marked

prolongation of P-R interval, and cardiac fibrillation followed by arrest within an

average of 69 and 85 minutes respectively. There was no significant A-V difference

for potassium during the control period. After the infusion of digitoxin, there was

a gradual increase in coronary sinus potassium with less rise in arterial potassium

concentration, indicating a significant negative A-V difference. Concurrently,

there appeared to be a greater uptake of sodium with a positive A-V difference.

Both cation A-V differences began to be significant from 60 minutes and reached

their maximum at the time of death.

After the death of the animals, an examination of the potassium content in

myocardium revealed a slight but significant decrease (307mEq/kg) compared to the

control value in the normal dogs (356mEq/kg). The myocardial sodium appeared to be

slightly increased and there was no significant change in the potassium and sodium

contents in the skeletal muscles.

2. In the dogs pretreated with cortisone for 14 days, the continuous infusion of

digitoxin produced a prolonged P-R interval and cardiac arrest in an average of 47

and 78 minutes respectively. The average lethal dose of digitoxin was 15.6mg/kg

which is significantly lower than that observed in the normal dogs (17.0mg/kg).

This result indicates that the pretreatment with cortisone definitely increased

sensitivity to the cardiac toxicity of digitoxin.

At the beginning of the experiment, these dogs showed a marked decrease in the

plasma potassium of arteral and coronary sinus blood and also showed insignificant

negative A-V difference. After the infusion of digitoxin, the potassium

concentrations in the coronary sinus and arterial blood showed a gradual rise,

maintaining the negative A-V difference. Concurrently, there was a significant

positive A-V difference in the plasma sodium concentrations. After the lethal dose

of digitoxin, the mean myocardial potassium of these animals was 271mEq/kg, which

represents a decrease of about 26mEq/kg over that of normal animals. Conversely,

the myocaridal sodium concentration was markedly increased.

3. In the animals pretreated with desoxycorticosterone, the continuous infusion

of digitoxin produced cardiac arrest within 44 minutes, indicating that

desoxycorticosterone causes more increase in the sentitivity of the lethal dose of

digitoxin than cortisone. The pretreatment with desoxycorticosterone produced a

significant decrease in the plasma potassium concentrations in the coronary sinus

and arterial blood, as did cortisone. After the infusion of digitoxin, the plasma

potassium concentrations showed a marked continuous increase, and there was no

significant change in the A-V difference except at the time just before the cardiac

arrest. The mean myocardial potassium was 248mEq/kg, which is a lower value

compared to that observed in the cortisone-treated animals. Conversely, the

myocardial sodium was increased twice as much as that in the normal dogs.

The above results confirm that cortisone and desoxycorticosterone enhance the

cardiotoxicity of digitoxin. It was also shown that the lethal dose of digitoxin

produced a loss of potassium from the myocardium and that pretreatment with

cortisone or desoxycorticosterone caused a significant decrease in the myocardial

potassium content. Therefore, it is concluded that the enhancement of cardiotoxic

activity of digitoxin by cortisone or desoxycorticosterone seems to be closely

related to the potassium content in the myocardium.

[영문]

Because of the similarity in the chemical structures of adrenocortical steroids and of digitalis aglycones, extensive studies have been reported concerning the cardiac activities of the cortical steroids. However, none of these steriods have

been shown to be a cardiostimulant as potent as digitalis glycosides. In the studies of the cardiac action of cortisone, Lee(1963) fround that cortisone itself does not produce any significant effects upon the heart, but that it does enhance

the cardiotoxic activity of digitoxin. Lown et al (1951) also reported that the animals treated with desoxycorticosterone for ten days showed a marked increase in susceptibility to the cardiotonic action of digitalis. In view of the recent

increase in the frequency of the administration of cortical steroids, there is an increasing possibility for a cardiac patient, particularly one who is receiving digitalis glycosides, to receive these steriods. In such a patient, unexpected

cardiac toxic manifestation may be produced by these drugs. Therefore, it seems to be worthwhile to study the mechanism by which cortical steroids potentiated to the cardiac toxicity of dgitalis glycosides.

It has long been known that adrenocortical steroids, particularly, desoxycorticosterone and aldosterone promote the urinary excretion of potassium resulting in a decrease in intracellular potassium content. On the other hand, although conflicting evidence has been presented in regard to the effects of digitalis on the potassium content, numerous investigators have found a diminished potassium in the myocardium after the administration of digitalis in toxic doses.

It is, therfore, reasonable to expect that potassium depletion would be an important factor in the mechanism by which cortical steroids potentiate the cardiac toxicity of digitalis.

In an attempt to elucidate the mechanism of potentiating effects on the cardiotoxic activity of digitoxin by cortisone, the present experiment was undertaken to obtain evidence with regards to the effect of these drugs on the myocardial potassium content.

Healthy mongrel dogs weighing approximately 10kg were ?mployed in this experiment. Under pentobarbital sodium (30mg/kg) anesthesia, tracheotomy was made for artificial respiration. Arterial blood pressure was contincously recorded on a smoked kymograph through a mercury manometer connected the left femoral artery.

Polyethylene tubes were inserted into the right femoral artery and vein respectively and a single lumen catheter, filled with heparin was placed via the external juglar vein in the coronary sinus to obtain blood samples. Heparin (5mg/kg) was administered to prevent clotting of blood. Digitoxin was delivered into the left femoral vien by a constant infusion pump at a rate of 0.2mg/kg/min until cardiac arrest ensued. Frequent electrocardiographic changes were recorded during the experiment. The coronary arterio-venous (A-V) difference of sodium and

potassium were determined as a measure of their net uptake by, or release from, the myocardium. After the deathe of animals, auricular and skeletal muscles were analyzed for sodium and potassium. The Patwin Flame Photometer was used for measuring potassium and sodium in the plasma and muscle.

The experimental animals were divided, at random, into the following three groups.

Group 1: 9 normal dogs.

Group 2: 5 dogs treated with cortisone acetate 2.0mg/kg intramusculary daily for 14 days.

Group 3: 5 dogs treated with desoxycorticosterone in a daily dose of 25mg for from 7 to 14 days.

Results and Discussion

1. In normal dogs the continuous infusion of digitoxin produced a marked prolongation of P-R interval, and cardiac fibrillation followed by arrest within an average of 69 and 85 minutes respectively. There was no significant A-V difference

for potassium during the control period. After the infusion of digitoxin, there was a gradual increase in coronary sinus potassium with less rise in arterial potassium concentration, indicating a significant negative A-V difference. Concurrently,

there appeared to be a greater uptake of sodium with a positive A-V difference. Both cation A-V differences began to be significant from 60 minutes and reached their maximum at the time of death.

After the death of the animals, an examination of the potassium content in myocardium revealed a slight but significant decrease (307mEq/kg) compared to the control value in the normal dogs (356mEq/kg). The myocardial sodium appeared to be slightly increased and there was no significant change in the potassium and sodium contents in the skeletal muscles.

2. In the dogs pretreated with cortisone for 14 days, the continuous infusion of digitoxin produced a prolonged P-R interval and cardiac arrest in an average of 47 and 78 minutes respectively. The average lethal dose of digitoxin was 15.6mg/kg

which is significantly lower than that observed in the normal dogs (17.0mg/kg). This result indicates that the pretreatment with cortisone definitely increased sensitivity to the cardiac toxicity of digitoxin.

At the beginning of the experiment, these dogs showed a marked decrease in the plasma potassium of arteral and coronary sinus blood and also showed insignificant negative A-V difference. After the infusion of digitoxin, the potassium concentrations in the coronary sinus and arterial blood showed a gradual rise,

maintaining the negative A-V difference. Concurrently, there was a significant positive A-V difference in the plasma sodium concentrations. After the lethal dose of digitoxin, the mean myocardial potassium of these animals was 271mEq/kg, which

represents a decrease of about 26mEq/kg over that of normal animals. Conversely, the myocaridal sodium concentration was markedly increased.

3. In the animals pretreated with desoxycorticosterone, the continuous infusion of digitoxin produced cardiac arrest within 44 minutes, indicating that desoxycorticosterone causes more increase in the sentitivity of the lethal dose of digitoxin than cortisone. The pretreatment with desoxycorticosterone produced a

significant decrease in the plasma potassium concentrations in the coronary sinus and arterial blood, as did cortisone. After the infusion of digitoxin, the plasma potassium concentrations showed a marked continuous increase, and there was no significant change in the A-V difference except at the time just before the cardiac arrest. The mean myocardial potassium was 248mEq/kg, which is a lower value compared to that observed in the cortisone-treated animals. Conversely, the myocardial sodium was increased twice as much as that in the normal dogs.

The above results confirm that cortisone and desoxycorticosterone enhance the cardiotoxicity of digitoxin. It was also shown that the lethal dose of digitoxin produced a loss of potassium from the myocardium and that pretreatment with

cortisone or desoxycorticosterone caused a significant decrease in the myocardial potassium content. Therefore, it is concluded that the enhancement of cardiotoxic activity of digitoxin by cortisone or desoxycorticosterone seems to be closely

related to the potassium content in the myocardium.