Effects of dibenzepine and imipramine on the isolated rat heart

EUROPEAN JOURNAL OF PHARMACOLOGY 14 (1971) 333-339. NORTH-HOLLAND PUBLISHING COMPANY

EFFECTS

OF DIBENZEPINE AND IMIPRAMINE ON THE ISOLATED RAT HEART

A. LANGSLET, W. GRINI JOHANSEN, M. RYG *, T. SKOMEDAL and I. 0YE Institute of Pharmacology, University of Oslo, Norway

Accepted 1 February 1971

Received 26 June 1970

A. LANGSLET, W. GRINI JOHANSEN, M. RYG, T. SKOMEDAL and I. OYE: Effects ofdibenzepine and imipramine on the isolated rat heart, European J. Pharmacol. 14 (1971) 333-339.

The tricyclic antidepressants, imipramine and dibenzepine and the local anaesthetic drug lidocaine were added to the recirculating perfusate in a rat heart perfusion apparatus. Each drug produced the following effects: (a) A dosedependent decrease in impulse generation and impulse conduction velocity. (b) A dose-dependent decrease in cardiac contractile force. (e) A dose-dependent decrease in coronary flow preceded by an increase at lower concentrations. (d) A dose-dependent decrease in potassium loss from the heart. (e) Potentiation of the imipramineinduced decrease in contractile force and coronary flow in the presence oflidocaine. Further, in the concentration range in wich the antidepressants produced their cardiac effects, they stabilized eryhrocytes against hypotonic lysis. The antidepressants and the local anaesthetic share this effect and the cardiac effects with a variety of drugs commonly referred to as membrane stabilizers. It is concluded that the membrane stabilizers probably change the properties of biomembranes in a common way, and that the cardiac effects are secondary to these changes. Tricyclic antidepressants Local anaesthetics Membrane stabilizers

Perfused rat heart Erythrocyte stabilization ECG

1. INTRODUCTION Changes in ECG-pattern and cardiac performance in patients given tricyclic antidepressants have been described by several authors (Kristiansen, 1961 ; Muller et al., 196l; Schou, 1962; Rasmussen and Kristiansen, 1963; Moorehead and Knox, 1965). These changes are characterized by prolongation o f the PQ-interval and the QT-interval, lowering of the T-wave and disturbances in the QRS complex, and resemble the changes caused by phenothiazine tranquillizers (Reinert and Hermann, 1960; Delay and Deniker, 1961 ; Teitelbaum, 1963; Kelly et al., 1963; Wilson and Reese, 1964; Hollister and Kosek, 1965; Ban and St. Jean, 1965). Qualitatively similar changes are also found in isolated hearts deprived of nervous and hormonal control. We have suggested that these * Institute of Aviation Medicine, Royal Norwegian Air Force.

Cardiac contractile force Coronary flow Ion fluxes

effects reflect the 'general membrane stabilizing action' of these compounds (Landmark et al., 1969; Langslet 1969, 1970 a,b). The term 'membrane stabilizer' is used here to designate chemical substances which protect erythrocytes and cell organelles against lysis and mechanical disruption (Seeman, 1966) and depress excitability in nerves and muscles (Shanes, 1958 a,b). This membrane stabilizing action is shared by a variety of pharmacological agents, e.g. alcohols, antiphlogistic drugs, antihistamines, neuroleptics, antiparkinson drugs, barbiturates, anaesthetics, /3-adrenoreceptor blockers, and quinidine. These drugs decrease impulse generation, impulse propagation, potassium efflux, and contractile force in the isolated heart (Landmark et al., 1969; Langslet, 1969, 1970 a,b). The present experiments were made to examine: (1) Whether two tricyclic antidepressants (imipramine and dibenzepine) have the general effects of mere-

334

A.Langslet et al., Cardiodepressiveaction of dibenzepine and imipramine

brane stabilizers in non-excitable cells (erythrocytes). (2) Whether the cardiac effects are similar to those of other membrane stabilizers. (3)Whether additive effects of the antidepressants and a well known membrane stabilizer (lidocaine) could be produced.

2. MATERIAL AND METHODS 2.1. Resistance of erythrocytes to osmotic hemolysis The hemolytic activity of the two drugs was studied in suspensions of human erythrocytes (5 percent by packed cell volume) in 0.45-0.50% NaC1. The cells were incubated in the dark for 1 hr, at 37°C, and the amount of hemoglobin in the supernatant was measured spectrophotometrically at 410nm. One hundred percent hemolysis (for reference) was achieved by freezing and thawing the cell suspension. 2.2. Perfusion experiments on the isolated rat heart

Male Wistar albino rats weighing from 300-350 g were used as heart donors. The hearts were removed under ether anaesthesia and rapidly transferred to icecold saline. Cannulation of the aorta was performed with the hearts submerged in saline to prevent air from entering the heart cavities and coronary arteries. After a pre-perfusion period the hearts were transferred to a recirculation unit, previously described (0ye, 1965). The perfusate (40 ml) was a modified Krebs Ringer bicarbonate solution (Langslet, 1970 a) to which was added, 180 mg/100 ml of glucose. It was continuously aerated with 95% 02 and 5% CO2. In the experiments on the hypothermic heart, calcium and potassium were removed from the perfusate and replaced by sodium. 2.2.1. Perfusion of the isolated beating heart at 32°C After a washout period of 3 min, the hearts were transferred to the recirculation circuit and perfused retrogradely for 30 min. Drugs or distilled water were added 15 min after initiation of the perfusion. Coronary flow was measured and ECG-tracings made at regular intervals as described previously (Langslet, 1969, 1970a). Coronary flow was calculated in ml/gww/min (gww = gram wet weight). Imipramine (11 hearts), dibenzepine (11 hearts), lidocaine (13 hearts) or dis-

tilled water (4 hearts) were added to a total of 39 hearts. 2.2.2. Perfusion of electrically driven heart and recording isovolumic contractions by a polyvinyl balloon in the left ventricular cavity at 32°C. After a washout period of 3 rain, the hearts were transferred to the recirculation unit and perfused for 31 min with a polyvinyl balloon inserted into the left ventricular cavity to record isovolumic contractile force, as described by Langslet (1970b). The hearts were paced with square wave pulses (amplitude 12V, duration 0.5 msec) at 180 beats/min. Drugs or distilled water were added 15 min after initiation of the perfusion. Recordings of left ventricular contractile force were continuously made and the coronary flow measured at regular intervals. Coronary flow was calculated in ml/gww/min. Imipramine (11 hearts), dibenzep. ine (11 hearts), lidocaine (10 hearts), imipramine lidocaine (10 hearts) or water (4 hearts) were added to a total of 46 hearts. 2.2.3. Perfusion of the asystolic heart with a perfu sion medium deprived of potassium and calcium al 16°C. After a washout period of 3 min, the hearts wet( transferred to the recirculation circuit and kept in ar asystolic state by lowering the temperature to 16°C The hearts were perfused for 20 min with and with out the drugs added in different concentrations prio to perfusion. At regular intervals 1 ml of the perfu sion medium was removed for potassium assay. Th~ total potassium loss was calculated in mg/gdw/miJ (gdw = gram dry weight: hearts dried at 95°C fo 48 hr). Imipramine (8 hearts), dibenzepine (9 heartsl lidocaine (8 hearts) or distilled water (8 hearts) wer added to a total of 33 hearts. 2.2.4. Laboratory instruments and pharmacologic~ agents A Biotron laboratory stimulator was used for ca~ diac pacing, a Sanborn transducer connected to Hewlett Packard 7702B recorder for contractile forc recordings, and a Sanborn recorder model 320 fc ECG-tracings. Imipramine, dibenzepine and lidocaine were gene ously supplied from Dumex, Novo and Astra respe, tively.

A.Langslet et al., Cardiodepressive action of dibenzepine and imipramine

335

3. R E S U L T S

3. l . Drug effects on the lysis o f erythrocytes in hypotonic saline Imipramine and dibenzepine inhibited hemolysis in c o n c e n t r a t i o n s h i g h e r t h a n 10 -s more potent than dibenzepine a b o v e 5 x 10 -4 M ( i m i p r a m i n e ) a n d e p i n e ) , the drugs h a d a lytic e f f e c t

M; i m i p r a m i n e was In concentrations 5 x 10 -3 M ( d i b e n z (fig. 1).

3.2. Drug effects on the isolated perfused rat hearts 3.2.1. D r u g effects o n E C G T h e c o n t r o l s m a i n t a i n e d a regular sinus r h y t h m d u r i n g t h e p e r f u s i o n p e r i o d w i t h n o changes in ECGp a t t e r n . As s h o w n in figs. 2 a n d 3 a n d t a b l e 1, all the drugs caused a d o s e - d e p e n d e n t decrease in rate a n d conduction velocity (1/PQ). Both the QRS and QT intervals were increased. W i t h h i g h e r c o n c e n t r a t i o n s , partial a n d t o t a l A V - b l o c k a n d i d i o v e n t r i c u l a r r h y t h m a p p e a r e d . I m i p r a m i n e a n d d i b e n z e p i n e were a l m o s t e q u i p o t e n t in c h a n g i n g E C G a n d were m o r e p o t e n t

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Fig. 1. Dose-dependent inhibition of hypotonic haemolysis caused by imipramine an dibenzepine, and increase of lysis at higher concentrations. Erythrocytes were suspended in hypotonic saline (0.45%), with and without the drugs added. The degree of lysis was estimated by measuring the amount of Hgb released. The Hgb release is calculated as a percentage of controls (no drug added).

Table 1 The left ventricular systolic pressure in mm Hg (PVSP), the heart rate in beats per min (HR), the 1/PQ in sec (1/PQ) and the coronary flow in ml/g wet weight (CF) five min after addition of imipramine (I), dibenzepine (D), lidocaine (L) in different concentrations or imipramine and 1.5 × 10 -5 M lidocaine (I+L) to the perfusate. In controls, water was added as described in the legend to figs. 2 and 6. The table also shows the total potassium loss in mg/g dry weight × 10-~ during twenty rain ofperfusion with the drugs added in different concentrations. In controls, water was added as described in the legend to fig.8. The control values for all the parameters represent total range.

Drug I D L [+L I

D L [ D L [ E) L :+L )

Parameter LVSP LVSP LVSP LVSP HR HR HR I[PQ 1/PQ 1/PQ CF CF CF CF ~(+ K+ K÷

Molar drug concentrations Control

10 -6

2 × 1 0 -6

5×10 -6

101 101 101 I01 150 150 150 12.5 12.5 12.5 8 8 8 8 9 9 9

102 100 99 101 148 153 160 13 12.0 12.5 8.0 7.8 8.8 8.2 9.2 9.5 9.4

103 102

98 104 102 92 147 149

± 3 ± 3 ± 3 ± 3 ± 12 -+ 12 ± 12 -+ 2.5 ± 2.5 ± 2.5 ± 1 ± 1 ± 1 ± 1 ± 0.6 -+ 0.6 ± 0.6

103

12.5 12.3 7.9 7.6 8.4

8.9 8.4 8.9 7.9 9.1 9.0 8.8

10 -5 84 99 63 134 142 150 11.4 11.3 12.0 9.4 8.2 8.1 7.2 9.2 9.1

2×10 -s 35 83 102 20 110 128 154 9.0 10.0 13.1 9.6 9.3 9.6 6.9 6.8 8.2 8.9

3X10 -5 26 47 10 102 120 143 8.6 9.8 12.9 9.3 9.4 6.2 6.2 7.8 9.6

5X10 -5

10 -4

16 30 96 8 81 94 137 7.5 8.9 12.8 8.3 7.0 9.8 3.1 5.7 7.3 8.1

15 21 74 5 58 81 104 7.1 7.6 11.1 3.1 2.6 7.1 1.6 5.3 6.7 7.7

2X10 -4 14 18 51 44 63 83 5.0 6.8 9.9 1.5 1.4 2.4 5.2 6.3 6.8

5X10

26

68

6.4

6.2

A.Langslet et al., Cardiodepressive action of dibenzepine and imipramine

336

HEART RATE IN PER CENT OF CONTROL

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Fig. 2. Dose-response curves for drug induced decrease in heart rate as a percentage of the rate before addition of the drug. The curves are based on ECG recordings made prior to and 5 rain after addition. Each point represents one experiment. A total of 39 experiments were performed including 4 controls (water added). Only experiments with drug concentrations above 10 -6 M are shown in the figure. Lower concentrations had no effect on the ECG. Hearts which did not maintain sinus rhythm are also excluded.

Fig. 4. Changes in ECG induced by 10-5 M dibenzepine. The upper tracings were recorded before addition of the drug and

the lower tracings 5 rain after addition. Characteristically, the T-wave of the rat ECG normally appears directly after the QRS-complex. This is attributable to very rapid repolarization of the ventricular muscles in rats. Note the prolongation of the PQ-intervals, the changes in the QRS complexes and the T wave and the decrease in rate induced by dibezepine 10 -5 M.

t h a n lidocaine. S o m e e x a m p l e s o f t h e E C G changes are s h o w n in figs. 4 a n d 5. 3.2.2. Drug effects o n cardiac c o n t r a c t i l e force As s h o w n in fig. 6 an table 1, all t h e drugs c a u s e d a d o s e - d e p e n d e n t decrease in cardiac c o n t r a c t i l e force. T h e relative o r d e r o f p o t e n c y c a l c u l a t e d o n a m o l a r

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Fig. 3. Dose-response curves for drug induced decrease in conduction velocity (expressed as 1/PQ) as a percentage of the conduction velocity before addition of the drug. The curves are based on ECG recordings as described in legend to fig. 2.

Fig. 5. Changes in the ECG induced 2.5X10 -4 M imipramine The upper tracings were recorded before addition of thq drug, the middle tracings 2 min after addition and the lowe 5 rain after addition. Note the prolongation of the PQ-intei vals and the partial (2:1) AV block induced by imipramine : min after its addition to the perfusate, and the idioventricula rhythm induced 5 rain after its addition.

A.Langslet et al., Cardiodepressive action of dibenzepine and imipramine

basis was: imipramine > dibenzepine > lidocaine. If imipramine and lidocaine were added together, the effects on cardiac contractile force were potentiated (fig. 6). 3.2.3. Drug effects on coronary flow After 5 rain in the perfusion apparatus, coronary flow of the electrically paced heart was between 7 - 9 ml/gww/min. Coronary flow in control hearts did not change throughout the perfusion period. Drug effects on coronary flow in hearts paced at a fixed rate (180 beats/rain) are shown in fig. 7 and table 1. In low concentrations all the drugs increased coronary flow whereas in higher concentrations they decreased coronary flow. Imipramine and dibenzepine were almost equipotent in decreasing coronary flow and were more potent than lidocaine. When lidocaine 1.5 × 10-s M concn, was added together with different concentrations of imipramine, the dose-dependent decrease in coronary flow caused by imipramine was potentiated (fig. 7). Qualitatively similar effects of the drugs on coronary flow were observed in spontaneously beating hearts.

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Fig. 7. Dose-response curves for drug induced changes in coronary flow in electrically driven hearts. Coronary flow was recorded 5 min after addition of the drug, and calculated as a percentage of the flow at the time of addition of the drug. Each point represents one experiment. A total of 46 experiments were performed including 4 controls (water added). Experiments with drug concentrations below 10-6 M (which do not affect coronary flow) are not shown.

3.2.4. Drug effects on potassium effiux The hearts in this series were perfused at 16°C and they did not contract during the perfusion period. No , "trical impulses were recorded (ECG). The coron-

CARDIAC CONTRACTILE FORCE IN PER CENT OF CONTROL

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Fig. 6. Dose-response curves for drug induced decrease in cardiac contractile force as a percentage of the contractile force before addition of the drug. The curves are based on left ventricular pressure recordings made prior to and 5 min after addition. Each point represents one experiment. A total of 46 experiments were performed including 4 controls (water added). Only experiments with drug concentrations above 10-6 M are shown in the figure (lower concentrations did not change contractility).

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Fig. 8. Dose-response curves for drug induced changes in total potassium loss from hypothermic asystolic hearts, perfused for 20 rain, calculated as a percentage of the loss from control perfused hearts. Each point represents one experiment. A total of 40 experiments were performed including 8 controls (water added). Experiments with drug concentrations lower than 10--6 M (which did not change the potassium loss) are not shown in the figure.

338

A.Langslet et al., Cardiodepressive action o f dibenzepine and imipramine

ary flow did not change during the experimental period. As shown in fig. 8 and table 1 all the drugs tested caused a dose-dependent decrease in potassium loss. Calculated on a molar basis the relative order of potency was: Imipramine > dibenzepine > lidocaine.

4. DISCUSSION The present experiments show that both imipramine and dibenzepine cause a dose-dependent decrease in cardiac contractile force. A negative inotropic effect of imipramine has previously been observed in other in vitro preparations (Sigg et al., 1963; Arora and Lahiri, 1968; Prudhommeaux et al., 1968; Greef and Wagner, 1969) and in dogs in vivo (Sigg et al., 1963). In the concentrations which reduced cardiac contractile force, the drugs caused a dose-dependent decrease in cardiac rate, an increase in PQ-QRS and QT-intervals and a decrease in potassium loss from the hearts. The effects of imipramine and dibenzepine in the isolated organ were qualitatively identical to those produced by lidocaine; the effects of lidocaine and imipramine on contractile force and coronary flow were additive. The effects observed are not specific for the tricyclic anti-depressants and lidocaine, but are induced by a variety of drugs, e.g. other anaesthetics, alcohols, neuroleptics, antiphlogistics, antiparkinson drugs, barbiturates, antihistamines, and quirtidine (Vaughan Williams, 1958; Langslet, 1969; Landmark et al., 1969; Langslet, 1970a,b, for review see Langslet and 0ye, 1970). These drugs, including lidocaine, are membrane stabilizers as defined by Shanes (1958a,b), and decrease excitability in excitable cells. In addition, they share the ability to stabilize cells and particles against hypotonic and mechanical disruption and thus are membrane stabilizers as defined by Seeman (for review see Seeman, 1966). In the present work, it is shown that imiprarnine and dibenzepine are not exceptions in this respect. Greef and Wagner (1969) showed that various thymoleptics had local anaesthetic properties. It is therefore possible that all these drugs change the physical properties of biological membranes by a simular mechanism. This alteration of membrane properties may impede the exchange of ions thought to be responsible for excitabil-

ity and contractility. The decrease in ion efflux from the heart caused by imipramine, dibenzepine and lidocaine at membrane stabilizing concentrations support this hypothesis. Membrane stabilization as a cause of drug-induced depression of cardiac activity is suggested by the work of previous authors (Holland 1957; Shanes, 1958a,b; Holland et al., 1959 Klein et al., 1960; Klaus and Lullmann, 1961; van Zwieten, 1969; Nayler et al., 1969; Langslet, 1970a,b). Recordings of transmembrane potential in, isolated atria have revealed changes in the potentials caused by imipramine (Matsuo, 1967) as well as other membrane stabilizers (Vaughan Williams, 1958; Matsuo, 1967; Papp and Vaughan Williams, 1969; Landmark: personal communication) compatible with a general inhibition of ion fluxes. The present experiments show that imipramine, dibenzepine and lidocaine cause a dose-dependent decrease in coronary flow at higher concentrations, preceded by an increase at lower concentrations in the rat heart in vitro. A similar biphasic effect on coronary flow in isolated rat hearts has previously been observed with phenothiazine derivatives (Langslet, 1969; Landmark et al., 1969), anti-parkinson drugs and local anaesthetics (Langslet, 1970a). Sigg et al. (1963) found a similar biphasic effect on coronary flow induced by imipramine-infusion intravenously in anaesthetized dogs. Since hearts, in vitro are deprived of hormonal and nervous control, and since the effects of these drugs on coronary flow are also present in hearts maintained in a state of aystole by lowering the temperature (Langslet, 1970b and unpublished observations in our laboratories), a direct action on coronary resistance vessels is likely. The reported effects of imipramine, dibenzepine and lidocaine may have clinical implications. The changes in ECG-pattern observed in isolated rat heart preparations are similar to those observed in patients given tricyclic antidepressants (Kristiansen, 1961; Muller et al., 1961; Schou, 1962; Rasmussen and Kristiansen, 1963; Moorehead and Knox, 1965). These ECG-changes associated with reduction in cardiac performance are pronounced in cases of intoxication with these antidepressants. Lidocaine, and othe~ membrane stabilizers, sometimes used to treat cardiac arrhythmias, might possibly have a deleterious effecl in such patients.

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