Clinical and Experimental Pharmacology and Plz,vsiology (1 977) 4, 121- 129.
CARDIOVASCULAR EFFECTS OF AMITRIPTYLINE IN ANAESTHETIZED DOGS P. Dhumma-Upakorn and L. B. Cobbin Department of Pliarmacology, University of Sydnqv, New South Wales, Australia
(Received 21 September 1975)
SUMMARY
1 . The effect of amitriptyline on cardiovascular variables has been studied in anaesthetized dogs. 2. In small doses (0.25 mg/kg) amitryptyline caused small increases in heart rate, contractility, blood pressure, coronary blood flow and aortic flow. 3 . Larger doses produced initial depressant effects on myocardial contractility and rate and blood pressure, which were followed by secondary reflex rises in these measurements. 4. The depressant effects were dose-related and were accompanied by marked increases in coronary flow and smaller increases in aortic flow. 5 . The secondary reflex rises in cardiac parameters were abolished by propranolol and that of the blood pressure was much reduced. Key words: amitriptyline, aortic flow, blood pressure, coronary flow, heart rate, myocardial contractility, propranolol.
INTRODUCTION It is widely accepted that tricyclic antidepressant drugs interfere with noradrenaline uptake processes at the postganglionic sympathetic nerve ending. Because the tricyclic drugs also have a peripheral parasympathetic blocking action, vagal tone to the heart is diminished and may be responsible for tachycardia, which could be augmented by increased local concentration of noradrenaline. This combined-mechanism was suggested by Torchiana et al. (1 972) to explain the tachycardia and arrhythmias produced in anaesthetized dogs by amitriptyline and protriptyline and was based on evidence that anticholinesterases and the 0-adrenoceptor blocking drug, propranolol, reduced these disturbances. Tachycardia and arrhythmias which can have a fatal outcome are seen in man when overdoses of tricyclic antidepressants are consumed (Moir et al., 1972). Many cardiac arrhythmias can be successfully abolished by propranolol, but the drug has a cardiodepressant action which can precipitate acute congestive cardiac failure in patients with diminished cardiac reserve. Correspondence: Professor L. B. Cobbin, Department of Pharmacology, University of Sydney, Sydney, New South Wales 2006, Australia.
121
122
P. Dhumma-Upakorn and L. B. Cobbin
It was decided to study the effects of intravenous injections of amitriptyline upon myocardial contractility and rate, arterial blood pressure, cardiac output and coronary flow in anaesthetized dogs, and to investigate any interactions in these parameters with propranolol. METHODS Mongrel dogs ( I 0-22 kg) were anaesthetized with pentobarbitone sodium (30 mg/kg, i.v.) supplemented as required. The trachea was intubated and respiration assisted with a Bird Mark 8 respirator. A catheter was inserted into the right femoral artery and advanced to the descending aorta to measure arterial pressure when connected to a Statham P23 Db strain gauge transducer. Drugs were administered via a catheter in the right femoral vein. A left thoracotomy was performed at the fifth intercostal space and the heart was suspended in a cradle prepared from the incised pericardium. A stab incision was made through a purse string suture placed in the apex of the left ventricle taking care to avoid coronary arteries, and a Konigsberg P13 miniature implantable pressure transducer was inserted and tied into place. The pressure signal from the left ventricle was differentiated electronically but only the positive signal was recorded on the chart. The R-wave of the lead I1 electrocardiogram was used to trigger the onset of sampling and continuous integration of the left ventricular pressure. When max (dpldt) was detected, this value was stored by a peak read-and-hold circuit and simultaneously used to trigger off the integrated pressure signal (IIT or integrated isometric tension). The two signals max (dpldt) and IIT were passed to an analogue divider circuit and an output dp/dt -was recorded on the IIT polygraph as a measure of myocardial contractility (Siegel, 1969; Goodman et al., 1972). The computer was then reset by electronic relays and triggered by the next R-wave. As well as recording beat-by-beat contractility, an integrator was used to integrate each ten beats which were recorded on the polygraph chart. Heart rate was recorded using the lead I1 electrocardiogram to trigger a cardiotachometer. Ascending aortic and left circumflex coronary blood flows were recorded using an EM1 Type 28 electromagnetic flowmeter with flow probes selected to give a snug fit on the appropriate artery. Systemic conductance was measured by dividing the aortic flow signal by the aortic pressure signal using an analogue divider and coronary conductance was obtained similarly. In some experiments a cannula was advanced down the right common carotid artery to the aortic arch so that injections could be made intra-arterially. The interaction between propranolol and amitriptyline was investigated in one series of five dogs and compared with another group of five which received amitriptyline alone. Propranolol 0.5 mg/kg was administered and the effectiveness of @-adrenoceptor blockade was tested with a challenging dose of isoprenaline 0.1 pg/kg. Fifteen minutes after the proprano101, amitriptyline was administered and the myocardial contractility, heart rate and blood pressure responses recorded. All recordings were made with Grass 4 channel or 8 channel Model 7 polygraphs using standard Grass pre-amplifiers except for the contractility and voltage divider pre-amplifiers which were built and calibrated in the laboratory.
RESULTS The principal effects of amitriptyline on the cardiovascular system are summarized in Fig. 1, where the mean maximum percentage changes in the parameters measured are plotted
Cardiovasciilav depression by avliitriptyliize
123
against the dose administered. In higher doses there were usually biphasic responses and these have been shown as the initial effect on the left and the secondary effect on the right of each dose response column. The secondary effects were obtained within 5 min of the inj ection. At the lowest dose, 0.25 mg/kg, there was a small increase in myocardial contractility (1 3.5%, s.e.m. = 3.1, n = 8) in all the dogs. The duration of this increase varied but it had usually returned to pre-injection levels within 15 min. At all higher dose levels, some dogs in the group showed an initial fall in myocardial contractility which was dose dependent and ~. which was followed by a secondary increase in contractility reaching a maximum within 45 i-
-45L
m
El
0.25 0.5 Dose of amitriptylirie hydrochloride (mg/kg)
Fig. 1. The effects of graded intravenous doses of' amitriptyline upon myocardial contracti-
dpidt , heart
rate (HR}, mean aortic flow (MAF), blood pressure (BP) and mean 11T coronary flow (MCF), expressed as percentage variations from control levels in eight dogs. The bar indicates 1 s.e.m. lity
approximately 2 rnin. More dogs showed the initial reduction in contractility as the dose of amitriptyline was increased, and at the highest dose administered (4 mg/kg), this was the only response observed in seven of the eight animals (-30.3%, s.e.rn. = 4.8, n = 8). In the one dog which showed a secondary increase in contractility, the magnitude of the response was only 9%. Amitriptyline produced a modest increase in heart rate in doses of 0.25 mg/kg (17.9%, s.e.m. = 2.9, n = 8). Higher doses caused an initial fall in some dogs which was larger as the dose of the drug was increased. As in the case of myocardial contractility, the number of dogs exhibiting the initial reduction in heart rate increased with larger doses. All animals exhibited an increase in heart rate with doses of amitriptyline greater than 0.25 mg/kg but this increase became less as the dose of the drug was increased. When the dose was 2 mg/kg, the secondary tachycardia was transient and within 5 min of the injection, the heart rate had fallen below the control rate. Amitriptyline (0.25 mg/kg) caused a small increase in arterial blood pressure in all dogs, but in two of these it was preceded by a small but measurable reduction. At higher doses
124
P. Dhumma-Upakorn and L. B. Cobbin
there was a progressive increase in the magnitude of the maximum initial depressor response until at 4 mg/kg the fall in mean blood pressure was 51.6% (s.e.m. = 1.8, n = 8). The effect was more marked upon the diastolic pressure than the systolic. At the intermediate doses, 0.5 to 2.0 mg/kg, the initial reduction was followed by a small rise in blood pressure in some dogs, the number responding in this way becoming less as the dose was increased. The secondary rise occurred about 2 min after the injection and, at doses in excess of 1 mg/kg, was followed by a further fall below control levels. The duration of this tertiary fall varied from dog to dog and was commonly 15-30 min. At 4 mg/kg the control blood pressure was not regained in some experiments. Between 0.25 and 2 mg/kg, amitriptyline produced progressive increases in mean aortic flow, although at 2 mg/kg there was an initial transient reduction of the order of 5% during the period of the initial fall in aortic blood pressure. The duration of the increased flow was short and usually it had returned to its pre-injection level within 3 min. In some dogs this dose produced a further fall in aortic blood flow. Doses of 4 mg/kg amitriptyline produced variable effects upon aortic blood flow, and these were determined by the precise effects upon myocardial contractility, heart rate and blood pressure at any given instant. Nevertheless, within 3 min of administration of the drug, the mean aortic flow was decreased below control levels. The effects of amitriptyline on systemic conductance were seen at all dose levels greater than 0.5 mg/kg. There was a dose-dependent increase in systemic conductance, although at 4 mg/kg the variability in aortic flow responses produced a similar degree of variability in the aortic conductance and no constant pattern was observed. At dose levels between 0.5 and 2 mg/kg, the initial increase in conductance was followed by a reduction to below control readings whose duration was determined by the durations of the effects upon blood pressure and aortic flow. In some dogs the effects of amitriptyline were also observed upon the coronary arterial flow and coronary conductance. Following injection of the drug, effects upon coronary flow were the first to be observed occurring some 3-5 s prior to any other responses. The increase in coronary flow was dose-dependent (see Fig. 1 ) and was more than doubled at 4 mg/kg. The duration of this effect, however, was relatively short-less than 1 min-and when the dose exceeded I mg/kg was followed by a reduction in flow whose duration depended upon the duration of the reduction in aortic blood pressure (see Fig. 2). Conductance through the coronary arteries was dramatically increased by the larger doses of amitriptyline to a much greater degree than the coronary flow itself. Even when the coronary flow had fallen below pre-injection values, the coronary conductance remained elevated despite the fall in aortic blood pressure (Fig. 2). In some experiments amitriptyline was injected into the aorta via a catheter pushed down the carotid artery. In this way, the effects of the drug upon the circulation could be observed before it reached the heart. A sample recording is shown in Fig. 3 where it can be seen that the drug caused a fall in coronary blood flow which paralleled the fall in aortic blood pressure. It is also apparent that there was little change in the coronary conductance initially, but when the drug reached the heart there was a slight rise in both coronary flow and conductance. Figure 3 also shows, for comparison, the effects of the same dose of amitryptyline upon the coronary circulation when injected intravenously. The increase in coronary flow and conductance is accompanied by an initial bradycardia which is followed by an increase above pre-injection levels and an increase in myocardial contractility. The increases in myocardial contractility, heart rate and mean aortic flow produced by
125
Cardiovascular depression by amitrip t y line 0.8r
(ml/min/mmHg) conductonce Coronory o 0.4
lmin I
.
-
[
l
0.2
0 Coronory
Fig. 2. The effects of amitriptyline (4 mg/kg) on the coronary conductance, coronary blood flow and blood pressure in an anaesthetized dog.
o’s
.I .m. ,i, n..
1.5
I
( s - 2 ) x 10-4
Heart rate (beatshin) Coronory bloodflow
(ml/rnin)
,-”\
8oL
1-”o~ 75
Coronary 0 . 7 5 r conductonce 0.5 (rnl/min/rnmHg)
t I i.a
I i.v. Amitriptyline (2mg/kg)
Fig. 3. The effects of amitriptyline 2 mg/kg on myocardial contractility
dpldt
,heart 1IT rate, coronary flow, coronary conductance and blood pressure in an anaesthetized dog. In the left panel the drug was administered into the aortic arch, and in the right panel it was given via the femoral vein.
very low doses of amitriptyline (0.25 mg/kg) were abolished by propranololO.5 mg/kg. This same dose of propranolol abolished the secondary rises in contractility and heart rate and reduced the magnitude of the secondary rise in blood pressure following larger doses of amitriptyline (2 mg/kg; see Table 1). Propranolol did not modify coronary flow responses to amitriptyline. In a group of five dogs, the effects of 2 mg/kg amitriptyline were assessed upon the myocardial contractility, heart rate and arterial blood pressure. The mean percentage changes from control values and standard errors of these determinations, are shown in Table 1. In another group of five dogs, the effects of propranolol 0.5 mg/kg were assessed on the same variables. This dose was shown to abolish the effects of isoprenaline 0.1 pg/kg. Fifteen
P
Group 1 ( n = 5) Amitriptyline 2 mg/kg Group 2 (n = 5 ) Propranolol Amitriptyline 2 mg/kg
3.7
s.e.m.
-10.3 1.8 41.5 7.8
CARDIOVASCULAR EFFECTS OF AMITRIPTYLINE IN ANAESTHETIZED DOGS P. Dhumma-Upakorn and L. B. Cobbin Department of Pliarmacology, University of Sydnqv, New South Wales, Australia
(Received 21 September 1975)
SUMMARY
1 . The effect of amitriptyline on cardiovascular variables has been studied in anaesthetized dogs. 2. In small doses (0.25 mg/kg) amitryptyline caused small increases in heart rate, contractility, blood pressure, coronary blood flow and aortic flow. 3 . Larger doses produced initial depressant effects on myocardial contractility and rate and blood pressure, which were followed by secondary reflex rises in these measurements. 4. The depressant effects were dose-related and were accompanied by marked increases in coronary flow and smaller increases in aortic flow. 5 . The secondary reflex rises in cardiac parameters were abolished by propranolol and that of the blood pressure was much reduced. Key words: amitriptyline, aortic flow, blood pressure, coronary flow, heart rate, myocardial contractility, propranolol.
INTRODUCTION It is widely accepted that tricyclic antidepressant drugs interfere with noradrenaline uptake processes at the postganglionic sympathetic nerve ending. Because the tricyclic drugs also have a peripheral parasympathetic blocking action, vagal tone to the heart is diminished and may be responsible for tachycardia, which could be augmented by increased local concentration of noradrenaline. This combined-mechanism was suggested by Torchiana et al. (1 972) to explain the tachycardia and arrhythmias produced in anaesthetized dogs by amitriptyline and protriptyline and was based on evidence that anticholinesterases and the 0-adrenoceptor blocking drug, propranolol, reduced these disturbances. Tachycardia and arrhythmias which can have a fatal outcome are seen in man when overdoses of tricyclic antidepressants are consumed (Moir et al., 1972). Many cardiac arrhythmias can be successfully abolished by propranolol, but the drug has a cardiodepressant action which can precipitate acute congestive cardiac failure in patients with diminished cardiac reserve. Correspondence: Professor L. B. Cobbin, Department of Pharmacology, University of Sydney, Sydney, New South Wales 2006, Australia.
121
122
P. Dhumma-Upakorn and L. B. Cobbin
It was decided to study the effects of intravenous injections of amitriptyline upon myocardial contractility and rate, arterial blood pressure, cardiac output and coronary flow in anaesthetized dogs, and to investigate any interactions in these parameters with propranolol. METHODS Mongrel dogs ( I 0-22 kg) were anaesthetized with pentobarbitone sodium (30 mg/kg, i.v.) supplemented as required. The trachea was intubated and respiration assisted with a Bird Mark 8 respirator. A catheter was inserted into the right femoral artery and advanced to the descending aorta to measure arterial pressure when connected to a Statham P23 Db strain gauge transducer. Drugs were administered via a catheter in the right femoral vein. A left thoracotomy was performed at the fifth intercostal space and the heart was suspended in a cradle prepared from the incised pericardium. A stab incision was made through a purse string suture placed in the apex of the left ventricle taking care to avoid coronary arteries, and a Konigsberg P13 miniature implantable pressure transducer was inserted and tied into place. The pressure signal from the left ventricle was differentiated electronically but only the positive signal was recorded on the chart. The R-wave of the lead I1 electrocardiogram was used to trigger the onset of sampling and continuous integration of the left ventricular pressure. When max (dpldt) was detected, this value was stored by a peak read-and-hold circuit and simultaneously used to trigger off the integrated pressure signal (IIT or integrated isometric tension). The two signals max (dpldt) and IIT were passed to an analogue divider circuit and an output dp/dt -was recorded on the IIT polygraph as a measure of myocardial contractility (Siegel, 1969; Goodman et al., 1972). The computer was then reset by electronic relays and triggered by the next R-wave. As well as recording beat-by-beat contractility, an integrator was used to integrate each ten beats which were recorded on the polygraph chart. Heart rate was recorded using the lead I1 electrocardiogram to trigger a cardiotachometer. Ascending aortic and left circumflex coronary blood flows were recorded using an EM1 Type 28 electromagnetic flowmeter with flow probes selected to give a snug fit on the appropriate artery. Systemic conductance was measured by dividing the aortic flow signal by the aortic pressure signal using an analogue divider and coronary conductance was obtained similarly. In some experiments a cannula was advanced down the right common carotid artery to the aortic arch so that injections could be made intra-arterially. The interaction between propranolol and amitriptyline was investigated in one series of five dogs and compared with another group of five which received amitriptyline alone. Propranolol 0.5 mg/kg was administered and the effectiveness of @-adrenoceptor blockade was tested with a challenging dose of isoprenaline 0.1 pg/kg. Fifteen minutes after the proprano101, amitriptyline was administered and the myocardial contractility, heart rate and blood pressure responses recorded. All recordings were made with Grass 4 channel or 8 channel Model 7 polygraphs using standard Grass pre-amplifiers except for the contractility and voltage divider pre-amplifiers which were built and calibrated in the laboratory.
RESULTS The principal effects of amitriptyline on the cardiovascular system are summarized in Fig. 1, where the mean maximum percentage changes in the parameters measured are plotted
Cardiovasciilav depression by avliitriptyliize
123
against the dose administered. In higher doses there were usually biphasic responses and these have been shown as the initial effect on the left and the secondary effect on the right of each dose response column. The secondary effects were obtained within 5 min of the inj ection. At the lowest dose, 0.25 mg/kg, there was a small increase in myocardial contractility (1 3.5%, s.e.m. = 3.1, n = 8) in all the dogs. The duration of this increase varied but it had usually returned to pre-injection levels within 15 min. At all higher dose levels, some dogs in the group showed an initial fall in myocardial contractility which was dose dependent and ~. which was followed by a secondary increase in contractility reaching a maximum within 45 i-
-45L
m
El
0.25 0.5 Dose of amitriptylirie hydrochloride (mg/kg)
Fig. 1. The effects of graded intravenous doses of' amitriptyline upon myocardial contracti-
dpidt , heart
rate (HR}, mean aortic flow (MAF), blood pressure (BP) and mean 11T coronary flow (MCF), expressed as percentage variations from control levels in eight dogs. The bar indicates 1 s.e.m. lity
approximately 2 rnin. More dogs showed the initial reduction in contractility as the dose of amitriptyline was increased, and at the highest dose administered (4 mg/kg), this was the only response observed in seven of the eight animals (-30.3%, s.e.rn. = 4.8, n = 8). In the one dog which showed a secondary increase in contractility, the magnitude of the response was only 9%. Amitriptyline produced a modest increase in heart rate in doses of 0.25 mg/kg (17.9%, s.e.m. = 2.9, n = 8). Higher doses caused an initial fall in some dogs which was larger as the dose of the drug was increased. As in the case of myocardial contractility, the number of dogs exhibiting the initial reduction in heart rate increased with larger doses. All animals exhibited an increase in heart rate with doses of amitriptyline greater than 0.25 mg/kg but this increase became less as the dose of the drug was increased. When the dose was 2 mg/kg, the secondary tachycardia was transient and within 5 min of the injection, the heart rate had fallen below the control rate. Amitriptyline (0.25 mg/kg) caused a small increase in arterial blood pressure in all dogs, but in two of these it was preceded by a small but measurable reduction. At higher doses
124
P. Dhumma-Upakorn and L. B. Cobbin
there was a progressive increase in the magnitude of the maximum initial depressor response until at 4 mg/kg the fall in mean blood pressure was 51.6% (s.e.m. = 1.8, n = 8). The effect was more marked upon the diastolic pressure than the systolic. At the intermediate doses, 0.5 to 2.0 mg/kg, the initial reduction was followed by a small rise in blood pressure in some dogs, the number responding in this way becoming less as the dose was increased. The secondary rise occurred about 2 min after the injection and, at doses in excess of 1 mg/kg, was followed by a further fall below control levels. The duration of this tertiary fall varied from dog to dog and was commonly 15-30 min. At 4 mg/kg the control blood pressure was not regained in some experiments. Between 0.25 and 2 mg/kg, amitriptyline produced progressive increases in mean aortic flow, although at 2 mg/kg there was an initial transient reduction of the order of 5% during the period of the initial fall in aortic blood pressure. The duration of the increased flow was short and usually it had returned to its pre-injection level within 3 min. In some dogs this dose produced a further fall in aortic blood flow. Doses of 4 mg/kg amitriptyline produced variable effects upon aortic blood flow, and these were determined by the precise effects upon myocardial contractility, heart rate and blood pressure at any given instant. Nevertheless, within 3 min of administration of the drug, the mean aortic flow was decreased below control levels. The effects of amitriptyline on systemic conductance were seen at all dose levels greater than 0.5 mg/kg. There was a dose-dependent increase in systemic conductance, although at 4 mg/kg the variability in aortic flow responses produced a similar degree of variability in the aortic conductance and no constant pattern was observed. At dose levels between 0.5 and 2 mg/kg, the initial increase in conductance was followed by a reduction to below control readings whose duration was determined by the durations of the effects upon blood pressure and aortic flow. In some dogs the effects of amitriptyline were also observed upon the coronary arterial flow and coronary conductance. Following injection of the drug, effects upon coronary flow were the first to be observed occurring some 3-5 s prior to any other responses. The increase in coronary flow was dose-dependent (see Fig. 1 ) and was more than doubled at 4 mg/kg. The duration of this effect, however, was relatively short-less than 1 min-and when the dose exceeded I mg/kg was followed by a reduction in flow whose duration depended upon the duration of the reduction in aortic blood pressure (see Fig. 2). Conductance through the coronary arteries was dramatically increased by the larger doses of amitriptyline to a much greater degree than the coronary flow itself. Even when the coronary flow had fallen below pre-injection values, the coronary conductance remained elevated despite the fall in aortic blood pressure (Fig. 2). In some experiments amitriptyline was injected into the aorta via a catheter pushed down the carotid artery. In this way, the effects of the drug upon the circulation could be observed before it reached the heart. A sample recording is shown in Fig. 3 where it can be seen that the drug caused a fall in coronary blood flow which paralleled the fall in aortic blood pressure. It is also apparent that there was little change in the coronary conductance initially, but when the drug reached the heart there was a slight rise in both coronary flow and conductance. Figure 3 also shows, for comparison, the effects of the same dose of amitryptyline upon the coronary circulation when injected intravenously. The increase in coronary flow and conductance is accompanied by an initial bradycardia which is followed by an increase above pre-injection levels and an increase in myocardial contractility. The increases in myocardial contractility, heart rate and mean aortic flow produced by
125
Cardiovascular depression by amitrip t y line 0.8r
(ml/min/mmHg) conductonce Coronory o 0.4
lmin I
.
-
[
l
0.2
0 Coronory
Fig. 2. The effects of amitriptyline (4 mg/kg) on the coronary conductance, coronary blood flow and blood pressure in an anaesthetized dog.
o’s
.I .m. ,i, n..
1.5
I
( s - 2 ) x 10-4
Heart rate (beatshin) Coronory bloodflow
(ml/rnin)
,-”\
8oL
1-”o~ 75
Coronary 0 . 7 5 r conductonce 0.5 (rnl/min/rnmHg)
t I i.a
I i.v. Amitriptyline (2mg/kg)
Fig. 3. The effects of amitriptyline 2 mg/kg on myocardial contractility
dpldt
,heart 1IT rate, coronary flow, coronary conductance and blood pressure in an anaesthetized dog. In the left panel the drug was administered into the aortic arch, and in the right panel it was given via the femoral vein.
very low doses of amitriptyline (0.25 mg/kg) were abolished by propranololO.5 mg/kg. This same dose of propranolol abolished the secondary rises in contractility and heart rate and reduced the magnitude of the secondary rise in blood pressure following larger doses of amitriptyline (2 mg/kg; see Table 1). Propranolol did not modify coronary flow responses to amitriptyline. In a group of five dogs, the effects of 2 mg/kg amitriptyline were assessed upon the myocardial contractility, heart rate and arterial blood pressure. The mean percentage changes from control values and standard errors of these determinations, are shown in Table 1. In another group of five dogs, the effects of propranolol 0.5 mg/kg were assessed on the same variables. This dose was shown to abolish the effects of isoprenaline 0.1 pg/kg. Fifteen
P
Group 1 ( n = 5) Amitriptyline 2 mg/kg Group 2 (n = 5 ) Propranolol Amitriptyline 2 mg/kg
3.7
s.e.m.
-10.3 1.8 41.5 7.8
