Modification in dogs of the systemic and coronary hemodynamic effects of glucagon by sotalol

Modification hemodynamic

in dogs effects

of the systemic and coronary of glucagon by sotalol

Theodore B. Berndt, M.D. Thomas J. Ansjield, M.D. Skoda Aljonso, M.D. George G. Rowe, M.D. Madison, Wis.

T

he systemic hemodynamic effects of glucagon in man, 1-3 the intact anima1,4-6 and the isolated animal organ preparation4*5t1*8 have been previously described. The mechanism by which glucagon exerts its effect is not clear. Several investigators have reported that most or all of the hemodynamic effects of glucagon are unaffected by prior beta-blockade with propranolol.4-6 Sotalol (dl 4-[2-isopropylamino-l-hydroxyethyl] methane Sulfonanilide-HCI, MJ 1999) has been reported to be a beta adrenergic receptor blocking agent free of any intrinsic adrenergic activity.g Its coronary and systemic hemodynamic effects have been extensively studied and reported.‘O-I5 We are not aware, however, of any report of the combined hemodynamic effects of glucagon and sotalol. In this communication we report our findings of the hemodynamic effects of the interaction of beta adrenergic receptor blockade with

sotalol and the intravenous administration of glucagon in the anesthetized dog. Materials

and

methods

A total of 18 anesthetized mongrel dogs were studied. They received 3 mg. per kilogram of body weight of morphine sulfate subcutaneously followed one hour later by the intravenous administration of 0.25 ml. per kilogram of body weight of SO/50 mixture of veterinary pentobarbital and dialurethane.* During the following hour cardiac catheters were manipulated under fluoroscopy into the pulmonary artery, right atrium, and coronary sinus, and a needle was inserted percutaneously into the femoral artery. A cuffed endotracheal tube was inserted into the trachea and the dog respired with room air by a Stephenson Model 1600 controlled respiration unit. The oxygen content of blood from the femoral and pulmonary arteries and the

From

the Cardiovascular Research Laboratory. Department of Medicine, University of Wisconsin Medical School, Madison, Wis. This research was supported in part by United States Public Health Service National Institutes of Health Grants HL 5364, HL 07754, HL 14928, and HL 5738. Received for publication July 10. 1972. Reprint requests to: George G. Rowe, M.D., Cardiovascular Research Laboratory. 420 N. Charter St.. Room 523. Madison, Wk. 53706. *Dial-urethane contains dial (diallybarbituric acid). 100 mg./ml.; monoethylurea. 400 n&ml.; and urethane. 400 mg./ml. Veterinary pentobarbital contains 60 mg./ml. of pentobarbital.

Vol.

85, No.

5, pp. 671-678

May,

1973

American Heart Journal

671

672

Am. Heavt J. May, 1973

Bern& et al.

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Fig. 1, A through F. A, I?, and C, The hemodynamic changes which occurred in seven dogs given glucagon (G) intravenously and then sotalol (S). For description see text. Changes are plotted on the ordinate as per cent change from control. Drug dosage and the average time of the observations in minutes are indicated on the abscissa. D, E, and F present in the same manner as above the hemodynamic changes which occurred in eleven

dogs given sotalol and then glucagon. For description see text. The symbols used with the control values for panels

A, B, and C and the units

in which

they

are expressed

are given

for each observation

as follows:

HR

=

heart rate in beats/minute (88); MF’ABP = mean pulmonary artery blood pressure (12 mm. Hg); MRABP = mean right atrial blood pressure (3 mm. Hg) ; MABP = mean arterial blood pressure (117 mm. Hg) ; CO = cardiac output (3.1 L./min.); RVW = right ventricular work (0.5 Kg. M./min.); LVW = left ventricular work (5.0 Kg. M./min.); TPuR = total pulmonary (3098 c.g.s. units); L VOpU = left ventricular (45 ml./min.); CVR = coronary vascular

resistance (302 c.g.s. units); oxygen usage (4.6 ml./min.);

TPeR CBF

= total peripheral = coronary sinus

resistance blood flow

resistance (2.7 units); and CS02 = coronary sinus oxygen content (8.0 ml./100 ml. of blood). These control values are given to indicate the general physiological status of the dogs at the beginning of the study.

coronary sinus was determined by the VanSlyke-Neil1 apparatus. Duplicate analyses were required to check within 0.2 ml. per 100 ml. of blood. Hemoglobin was determined with the Coleman Jr. Spectrophotometer. Cardiac output was determined by indicator dilution curves after injecting indocyanine green dye into the pulmonary artery and sampling through a Gilson dye

tracer from the femoral artery. Calculation of the usual hemodynamic parameters was done by standard formulae as has been detailed previously from this laboratory.‘” Coronary sinus blood flow was determined continuously with a thermodilution catheter flowmeter.17 In all dogs control observations were made approximately one hour after the intravenous anesthetic had been

vOiwmea5

Number

Modi$cation

5

CONTROL 200,

MJ 1999 2.5mg.lkg. J---

GLUCAGON 50m./kg. J-

ARTERY

(mm

of glucagon

by sotalol

673

IO MIN. AFTER GLUCAGON 5Qw./kg.

Hg.)

25 20 15 IO 5

--p-ci-EARGE RIGHT ATRIUM

(mm

Hg.)

~~JjJlJJJ~~~

ELECTROCARDIOGRAM Fig. 2. This figure is a representative series of tracings photographed from the record of one of the dogs which received sotalol (MJ 1999) and then glucagon intravenously. In the upper panel is a recording taken directly from the femoral artery revealing the systemic arterial pressure in millimeters of mercury. The paper recording speed was constant throughout so the change in heart rate and in pressure is obvious. The other tracings are as indicated. The composite picture of hemodynamic deterioration is very different from that seen after giving propranolol and then glucagon.

given, and observations were made as detailed below at intervals subsequent to sotalol and glucagon. Each dog served as his own control for each parameter. In the first seven dogs (Group A) glucagon was given first followed by sotalol. A bolus of glucagon 25 to 50 pg per kilogram of body weight was injected into the pulmonary artery and followed by an infusion of 50 to 100 pg per kilogram of body weight of glucagon into a foreleg vein throughout the duration of the experiment (approximately twenty minutes). Three to five minutes after the glucagon bolus had been given in six dogs, 5.0 mg. per kilogram of body weight of sotalol was injected into the pulmonary artery as a bolus. One dog was given a 2.5 pg per kilogram of body weight bolus of sotalol into the pulmonary artery followed by a foreleg infusion of 2.5 mg. per kilogram of body weight during the rest of the experiment with results similar to the other six dogs. In the next 11 dogs (Group B) sotalol was given first and then followed by glucagon. Sotalol was given in a bolus 2.5 mg. per kilogram of body weight into the pulmonary artery followed by an intravenous

infusion of 2.5 mg. per kilogram of body weight throughout the rest of the experiment. Two to eight minutes after the sotalol bolus had been given 50 pg per kilogram of body weight of glucagon was given as a bolus into the pulmonary artery followed by a foreleg intravenous infusion of 50 pg per kilogram of body weight throughout the rest of the experiment. Various hemodynamic parameters were followed at intervals as indicated in the graphed results. For technical reasons hemodynamic measurements were not made at identical times in each dog but the response was sufficiently similar that the continuously changing events could be reconstructed by grouping data. The average of the observations made for each period of time for the various parameters is indicated in the figures along with a symbol indicating the statistical significance of the change from the control observations. Results In the first seven dogs (Group A) glucagon was given first and was followed by administration of sotalol. In these animals the cardiac rate rose very promptly after

674

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Berndt et al.

the glucagon and remained high throughout the period of observation of glucagon effect. With the administration of sotalol a further considerable increase occurred as seen in Fig. lA, and the rate remained very rapid throughout the rest of the study. The mean systemic arterial blood pressure declined slightly after the glucagon and continued to decrease after administration of sotalol until the end of the study. Although mean pulmonary arterial pressure tended to rise subsequent to glucagon and to decline subsequent to the sotalol these changes were not significant. Right atria1 pressure fluctuated somewhat lower subsequent to glucagon, but without a statistically significant change. Subsequent to sotalol the decrease in right atria1 pressure became significant. As seen in Fig. lB, cardiac output rose acutely subsequent to glucagon administration and remained elevated until sotalol was given when it declined sharply returning essentially to control levels. Left and right ventricular work paralleled the changes in cardiac output, whereas total peripheral and pulmonary resistances fell significantly subsequent to glucagon and they tended to rise again toward control subsequent to the administration of sotalol. Fig. 1C reveals that coronary blood flow rose slightly subsequent to glucagon, but tended to return toward control prior to the administration of sotalol. After sotalol coronary flow decreased again to the control level. The coronary vascular resistance decreased sharply subsequent to glucagon and then rose gradually toward control returning rapidly toward the control value subsequent to sotalol. The coronary sinus oxygen content decreased subsequent to glucagon and continued to fall after administration of sotalol. Calculated cardiac oxygen consumption increased with glucagon and then decreased toward normal subsequent to sotalol. Thus in general, the stimulatory effect of glucagon on cardiac output, cardiac work, and coronary blood flow appeared to be neutralized by sotalol, while cardiac rate continued to rise significantly and pressures in the systemic and pulmonary arteries and in the right atrium continued to decline. Thus on each parameter except rate, the drugs were antagonistic.

In the 11 dogs known as Group B in which sotalol was administered first and was then followed by glucagon, significant changes also occurred as illustrated in Figs. lD, lE, and 1 F. Sotalol administration was accompanied by a transient sympathicomimetic effect in which tachycardia was accompanied by peripheral and pulmonary vasodilatation and a marked rise in cardiac output, right and left ventricular work (Fig. 1D). This effect was very transient and was accompanied by an increase in coronary blood flow and a decrease in coronary vascular resistance. When glucagon was given to these animals after beta adrenergic receptor blockade had been established by sotalol there was a very marked increase in cardiac rate with the average cardiac rate reaching about 2 10 beats per minute. This was accompanied by a continuing decrease in blood pressure in the systemic and pulmonary arteries and in the right atrium. Cardiac output rose transiently with glucagon administration (Fig. lE), accompanied by a transitory increase in right and left ventricular work and a decrease in systemic and pulmonary vascular resistance. However, this was followed shortly by a continuing decrease in right and left ventricular work accompanied by rising peripheral and pulmonary vascular resistance and rapid deterioration of the animal. The changes in the coronary circulation immediately after sotalol administration revealed a transitory increase in flow and a decrease in resistance (Fig. 1F). Subsequent to glucagon a second transitory increase in the coronary flow and a decrease in coronary resistance occurred and at the end of the experiment coronary sinus oxygen content decreased, coronary flow returned to normal, and coronary, peripheral, and pulmonary vascular resistance tended to rise again. As these dogs deteriorated the cardiac rate continued to be very rapid with continually falling systemic arterial, pulmonary arterial, and right atria1 pressures (see Fig. 2). Discussion

The hemodynamic effects of glucagon in the isolated animal organ preparation,4*5j7e8 in the intact dog,4-6,18and in humans’-3 have been well described. In general, glu-

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cagon in the present doses has a significant positive cardiac inotropic and chronotropic effect. Immediately after glucagon alone in these experiments, there was a significant increase in heart rate, cardiac output, and coronary blood flow and a significant decrease in total peripheral, pulmonary, and coronary vascular resistance. The increase in coronary blood flow was accompanied by an increase in arterial-coronary sinus oxygen difference and increased myocardial oxygen consumption. These data and that of otherslg suggest that glucagon causes an increase in coronary blood flow secondary to increased metabolic needs rather than by a direct effect on the coronary vessels. Moir and Nayler*O came to the same conclusion tlsing both a beating and arrested perfused isolated dog heart. The mechanism by which glucagon exerts its hemodynamic effect and why this is not blocked by propranolol is still not clear. Robison and associates*’ have suggested that in all tissue adenyl cyclase might be equivalent to the beta receptor. Differing experimental results may be due to specific end organ variation in the response of adenyl cyclase to catecholamines, beta adrenergic blockers, and glucagon. Levine and co-workers** have shown that large doses of exogenous adenosine 3’S’-monophosphate in man increased the cardiac output, heart rate, and blood pressure. LaRaia and associates23n8 found that in the perfused rat heart glucagon had a positive inotropic effect which was not paralleled by any changes in myocardial adenosine 3’,5’-monophosphate whereas l-epinephrine and 1-isoproterenol had a positive inotropic effect accompanied by increases in myocardial adenosine 3’,5’-monophosphate. Levey and Epstein,24 however, found that crystalline glucagon and norepinephrine increased the conversion of AT3*P to cyclic 3’,5’-AM3*P in particulate fractions of cat and human heart homogenates. D-L propranolol blocked this response to norepinephrine but not to glucagon. Furthermore, maximal doses of norepinephrine and glucagon were not additive on this conversion. They postulated therefore that there are two receptor sites in myocardial tissue which lead to activation of adenyl cyclase. One responds to glucagon, the other

Modification

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675

to norepinephrine. The myocardium, however, has only one adenyl cyclase enzyme responsive to these hormones. Murad and Vaughan25 showed that glucagon or epinephrine when added to washed particulate preparations of adenyl cyclase from rat heart catalyzed the formation of cyclic 3’,5’,-AMP from ATP. The glucagon reaction was not blocked by DC1 and propranolol as was the epinephrine reaction. Finally, Entman and colleagues26 found that glucagon, epinephrine, and all caused an increased cyclic 3’S’, -AMP calcium accumulation in sarcoplastic reticulum. Propranolol blocked this response to epinephrine but not to glucagon. They therefore suggested that the positive inotropic effects of epinephrine, glucagon, and cyclic 3’,5’,-AMP are all mediated by means of changes in the calcium pools of the sarcoplastic reticulum. It has not yet been determined where sotalol acts in this chain of events which finally causes a positive inotropic effect. Previous studies suggest that the hemodynamic effects of an intravenous bolus of 50 fig per kilogram of body weight of glucagon last 10 to 2.5 minutes,2*4t6 and therefore should have extended throughout the duration of the present experiments. This was insured further in the present study by a glucagon infusion. However, as can be seen from the present data, sotalol profoundly alters the effect of glucagon, the combination producing a very deleterious hemodynamic effect on the dog. Proprano101, on the other hand, does not alter the hemodynamic effects of glucagon significantly.4-6 It should be noted that this difference in response to propranolol and sota101 cannot be attributed to anesthetic agents since the same anesthetic was used in the preceding6 and in the present study. It is not clear why sotalol should differ from propranolol in the way it affects the hemodynamic changes produced by glucagon. They are both specific beta adrenergic blocking agents with peripheral and myocardial activity.*’ Some have suggested that there is more than one type of betareceptor. 27 Indeed Levey and Epstein24 suggest there are two myocardial receptor sites which lead to activation of adenyl cyclase.

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Data by Brooks and colleagues,13 Cohen and associates,28 and Rao and co-workerszg suggest that there are different and selective inotropic and chronotropic myocardial beta receptors with different affinities for sotalol. Perhaps propranolol and sotalol differ in their affinity for the receptors, thereby giving different results when combined with glucagon. In our own experience and that of others, the doses of sotalol used here give an adequate beta-blockade30-33 with a duration easily extending over the period of time of our experiments. 34 Previous studies have also indicated that sotalol is free of any intrinsic adrenergic activity.gs35 Our studies, however, showed that sotalol caused an immediate significant increase in cardiac output, coronary blood flow, and heart rate, as well as a significant decrease in total peripheral, pulmonary, and coronary vascular resistance, suggesting that it has intrinsic beta-adrenergic stimulating activity (see Figs. 20, 2E, and 2F). Studies by Blinks12 showed that in a cat papillary muscle preparation sotalol had an initial positive inotropic effect, and the data of Agarwal and colleagues36 suggest that sotalol has a central catecholamine releasing property in addition to its peripheral adrenergic activity. The intermediate results after sotalol agree with previous results from this laboratory and with those of other workers who have noted a negative inotropic effectI with comparable doses. This effect is probably secondary to its beta blocking property since sotalol is stated to be free of any local anesthetic or quinidine-like effect.32,37 The later hemodynamic deterioration of dogs after glucagon administration with prior beta blockade with sotalol was surprising. As previously stated, the positive inotropic and chronotropic effect of glucagon, with the dose and mode of administration used here, should still have been present at the end of these experiments. However, the combination of glucagon and sotalol caused a severe tachycardia which exceeded 200 per minute. Cobb and co-workers38 have shown the importance in dogs of beta receptor activity in the normal hemodynamic adjustment to paced heart

May,

J. 1973

rates in this range. In the presence of beta blockade with propranolol when the heart is paced at rates greater than 210 per minute cardiac output and coronary blood flow decreased and total peripheral and coronary vascular resistance increased very significantly. It has also been shown that sotalol causes a decrease in uptake of noradrenaline by tissue depleted of catecholamines by tyramine or reserpine and a decrease in the release of catecholamines by tyramine and nerve stimulation.3g These factors may explain why this combination of drugs has such a deleterious hemodynamic effect in dogs but do not explain why sotalol and propranolol differ so greatly in this respect. Some have suggested the use of glucagon for its inotropic effect in patients who have developed congestive heart failure from propranolol.4 Since sotalol is a more specific beta adrenergic blocker, without local anesthetic action,32,37 causes less myocardial depression,10~31~4n has a larger therapeutic index,1°b12 is more completely absorbed from the gastrointestinal tract,41 and is of longer duration34 than propranolol, it may well have some therapeutic advantages over propranolol. Our data, however, suggest that the combination of sotalol and glucagon has a deleterious hemodynamic effect on the anesthetized closed-chest dog. Until further studies have been done to clarify the mechanism involved in the interaction of these two drugs, their combined use in the therapy of man should be discouraged.

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