Modification of cardiac and hyperglycemic effects of epinephrine by insulin

Life Sciences Vol. 8, Part 1, pp . 551-558, 1969 Printed in Great Britain.

Pergamon Press

MODIFICATION OF CARDIAC AND HYPERGLYCEMIC EFFECTS OF EPINEPHRINE BY INSULIN Nathan Hiatt and Joseph Katz Department of Surgery and Cedars-Sinai Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90029 . (Received 22 January 1969 ; in final form 7 March 1969) WE have observed that treatment with oxytetracycline prolongs and intensifies the activity of insulin administered to pancreatectomized dogs ; and impairs their cardiac and hyperglycemic responses to a test dose of epinephrine .

These findings sug-

gested an antagonistic effect between insulin and epinephrine (1,2) .

In the present paper we show that the insulin-epinephrine

antagonism can be demonstrated in the blood glucose and cardiac responses of normal dogs . METHOD Twelve dogs of either sex, weighing between 12 and 20 kilos were divided into three groups :

6 experimental animals, 3

epinephrine controls and 3 insulin controls . for 24 hours before a test .

Each was fasted

One animal from each group was

tested while awake ; the rest were anesthetized with an intravenous injection of 25 mgm/kg sodium pentobarbital one hour before an experiment .

The electrocardiogram was monitored in

all the dogs . In the experimental dogs, after a specimen of venous blood for the determination of glucose was obtained and the heart rate recorded on the electrocardiogram, 0 .25 F/kg of Insulin (Regular Iletln(R) : Beef and Pork Zinc-Insulin Crystals) was injected intravenously .

The heart rate and force of the apex

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INSULIN-EPINEPHRINE INTERACTION

beat were recorded for 5 minutes.

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Another specimen for blood

glucose was then obtained and 25 fag/kg of epinephrine (Adrenalin Chloride) injected intravenously .

Following this injection

the heart rate and force of the apex beat were recorded at Intervals for five minutes .

Specimens of blood for glucose were

than obtained at appropriate periods for two hours.

Control

animals were treated exactly like experimental ones except that they received only one injection - either insulin or epinephrine . The force of the cardiac contraction was estimated. by palpation of the apex beat and quantitated on a scale ranging from 1t to 4+ .

Blood glucose was determined by a glucose oxidase

method (3)Results In control dogs injected with insulin the blood glucose de;6 creased by about 10;3 in 5 minutes and by a maximum of 5o-6o

GLUCOSE mg

'INSULIN AND EPINEPHRINE

FIG. 1 Typical experiments showing changes in blood glucose in three dogs .

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INSULIN-EPINEPHRINE INTERACTION

within 30 minutes .

553

The glucose remained at that level for half

an hour, and then began to rise, reaching the pre-injection value two hours after the injection (Fig . 1) . There was no change in the heart rate (Fig . 2) or force of the apex beat .

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FIG . 3 Electrocardiogram following 25 gradually subsided .

g/kg of epinephrine .

At the end of five minutes the heart rate

was generally elose'to the pre-injection value (Fig . 4) .

During

the period of tachyeardia the force of the apex beat rose quickly from 1+ to 4+ and as the heart rate fell, returned to 1+ .

In

these controls, the blood glucose doubled within five minutes of the injection and then fell to the pre-injection level during the next two hours (Fig . 1) .

INSULIN-EPINEPHRINE INTERACTION

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FrG . 4 Typical experiments showing changes in heart rate in two dogs . In the dogs injected with insulin five minutes before the epinephrine was given, the typical cardiac and blood glucose responses to epinephrine were considerably modified .

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no tachycardia; instead there was a moderate slowing of the heart rate (Fig . 5) for two-minutes . -.{, EPINEPHRINE y. -

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FIG . 5 Electrocardiogram following injection of epinephrine into animal pre-treated with insulin .

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555

After five minutes the heart rate was usually still below the pre-injection value (Fig . 4) .

The force of the apex beat in-

creased somewhat, to 2+, at the end of one minute and returned to 1+ after three minutes.

-The blood glucose showed the ex-

pected small drop after insulin but essentially no rise after epinephrine and a subsequent fall that was less than that of the insulin control dogs (Fig . 1) . The electrocardiogram following the injection of insulin showed no changes .

After epinephrine the changes were similar

to those that have been described by others (4) .

Following the

injection of epinephrine into dogs pre-treated with insulin, the changes in the electrocardiogram were less profound, fewer and of shorter duration than those in the epinephrine control dogs . The electrocardiographic changes will be described in more detail in another communication . In unanesthetized animals the pre-injection heart rate was considerably slower and the blood glucose lower then in anesthetized ones .

However, both anesthetized and unanesthetized ani-

mals responded in the sane way . Discussion The results of this experiment indicate that pre-treatment with insulin suppresses the effect of epinephrine on blood glucose and on the heart . Insulin, maximally active within thirty to sixty minutes, is thought to cause hypoglycemia by increasing uptake of glucose by muscle and fat tissue and by diminishing glucose output from the liver ($) .

Epinephrine, maximally active within five to ten

minutes, is believed to cause hyperglycemia by the glycogenolysis of liver and muscle glycogen and by inhibition of glucose utilization (5) .

Glycogenolysis of muscle glycogen liberates lactic

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INSULIN-EPINEPHRINE INTERACTION

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acid that is subsequently converted to glucose in the liver. In our experiment a single large dose of epinephrine was administered 5 minutes after the injection of only a moderate dose of insulin - when the blood glucose was but very slightly lowered . We expected a rapid rise of the blood glucose, followed by a quick fall - as the longer acting insulin continued its hypoglycemic activity .

Instead, we found that under the conditions

of our experiment the influence of epinephrine was suppressed and the influence of insulin less than in control animals suggesting that these hormones control blood glucose by common mechanisms .

This type of antagonism i .e . where each hormone

impairs the activity of the other, seems peculiar to insulin and epinephrine and does not exist between insulin and glucagon - a hormone whose action on the liver is believed to be the same as that of epinephrine .

It has been known for a long time that the

injection of insulin contaminated with glucagon is followed by

a

brief hyperglycemia before hypoglycemia appears.

And our own

studies show that, following the injection of glucagon into dogs pre-treated with insulin, the blood glucose rises considerably within 10 minutes and then quickly falls, as the injected insulin continues its hypoglycemic activity .

The influence of each

hormone on blood glucose seems unaffected by the other . An unexpected aspect of our findings was the extent to which insulin influences the response of the heart to epinephrine . After pre-treatment with insulin the positive inotropic effect of epinephrine, as measured by palpation of the apex beat, is largely obliterated and the positive chronotropic effect is absent .

There is, in fact, a slowing of the heart rate that

continues for two minutes - the duration of maximum tachycardia in control dogs .

We have no studies of the systemic blood

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557

Pressure nor of the effect of atropine on the relative bradycardia . In 1932 DeNayer (6) reported that continuous infusion of epinephrine for up to 150 minutes would prevent a significant change of blood glucose in rabbits injected intravenously with a single large dose of insulin .

He also noted the absence of

tachycardia following epinephrine injection into insulinized rabbits. The results of our experiment give no clue to the way in which insulin and epinephrine influence one another.

The effect

of insulin in antagonizing epinephrine is apparent within a few minutes, when the change in blood glucose is small, suggesting a direct action of the hormone .

Perhaps, in the liver, insulin

interferes with the activation of cyclic 3', 5' - AMP by epinephrine (but not by glucagon) .

Insulin repression of cyclic AMP

has been observed in the rat epididymal fat pad (7) ; studies on the lactate and FFA levels are in progress .

The mechanism

whereby insulin influences the cardiac effects of epinephrine is at present unclear, but this too may involve cyclic AMP since this co-factor may mediate the positive inotropic effect of catecholomines (8) .

The mechanism does not, however, involve

the insulin that was used - since an identical result was obtained with highly purified crystalline insulin in an unanesthetized dog . Preliminary experiments strongly suggest that insulin pretreatment also suppresses the positive chronotropic response to 10 pg/kg of isoproterenol and the hypertensive response to

0 .6 mg/kg of methoxamine . Summary After dogs are injected intravenously with epinephrine,

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558

there is considerable hyperglycemia and an increase in the rate and force of the heart beat .

However, if dogs are injected with

epinephrine five minutes after pre-treatment with insulin there is only a minimal rise in the blood glucose and no significant changes in the rate and force of the heart beat .

Our results

suggest that the insulin and epinephrine mechanisms may share a common site of action, not only in the liver but in the heart . Acloz owl edgmen ts We are grateful to Michael Katz and Alberto Gauna for technical assistance, and to Dr . Akinori Hayashi for interpretation of the electrocardiograms . This research was supported by NIH grant Ai : 10735-01 and by Mr . and Mrs . Gower Champion . References N . Hiatt, G . Bonorris and G . L . Lanchantin, unpublished data . 2.

. N . Hiatt, G . Bonorris and E . Coverdale, Proc . Soc . Exp . 31o1 ., 122, 489,(1966) . ,ed

3.

J . D. Teller, Abstr . Paper. 130th Leeting, p .69c .

Am . Chem .

Soc . (1956) . 4.

E . Lepeschkin and W . Raab, Federation Proceedings , 8, 94 (1949) .

5.

A. Gothe, Medical Pharmacology , 5 .493, p.99, 4th Ed .

C . V.

.Iosby Co ., St . Louis (1964) . 6.

P. P . DeFaver, Comp . Rend . Soc . Biol ., 111, 1049 (1932) .

7.

R. W . Butcher, J. G . T. SYteyd, C . R . Park and E .

. Sutherland,

Jr ., J . Biol . Chem ., 241, 1652 (1966) . 8.

A . Robinson, R . W . Butcher and E . W . Sutherland, Aim . Rev . Biochem.,

.2Z,

149 (1968) .