Europ.J.clin.Pharmacol. 8, 317-322 © by Springer-Verlag 1975
(1975)
Haemodynamic Effects of Intravenous Verapamil at Rest and during Exercise in Subjectively Healthy Middle-Aged Men J.-H. AtterhSg and L.-G. Ekelund Department
of Clinical Physiology,
Received: May 7, 1974,
accepted:
Karolinska Sjukhuset,
Stockholm,
Sweden
January ii, 1975
Summary, Verapamil, 0.I mg/kg body wt, was injected i.v. over 2 minutes in 8 subjectively healthy middle-aged men, followed by a continuous infusion of 0.007 mg/kg body wt per minute. Prior to the injection several of the subjects had raised pulmonary or systemic arterial pressures. At rest, the central pressures increased slightly, which was taken as a sign of a moderate negative inotropic effect, but there was no change in pre-ejection period or maximal dp/dt of the aortic pressure. The heart rate increased and there was a small decrease in systemic arterial pressure, probably due to a fall of systemic vascular resistance. The PQ time was prolonged. During exercise, with its positive inotropic stimulation, the moderate negative inotropic effect of verapamil disappeared, whereas the increase in heart rate and decrease in aortic pressures persisted. Some variables that reflected the oxygen demand of the heart decreased. The slight negative inotropic effect does not appear to be a particular contraindication to the use of verapamil, but it should be employed cautiously in conditions with a compensatory rise in systemic vascular resistance, or if atrioventricular conduction is impaired, Key words: Verapamil, haemodynamics,
exercise, man, vascular resistance,
In the past ten years interest has grown rapidly in compounds with a new mode of action, namely those which antagonise calcium effects in vascular smooth muscle and the heart, of which verapamil (Fleckenstein et al., 1967) is a well-known example. The indications for verapamil have steadily increased to its present extensive use (AtterhSg, 1969; Bender et al., 1966; Brittinger et al., 1970; Karnell and KShler, 1971; Schamroth et al., 1972). From clinical experience and a small number of haemodynamic investigations it is known that verapamil may have negative dromotropic, chronotropic and inotropic effects (Fleckenstein et al., 1967; Haas and H~rtfelder, 1962; Nayler et al., 1968; Ryd~n and Saetre, 1971; Schamroth, 1971; Singh and Vaugham Williams, 1972). However, studies in man at rest have been few and in part controversial and the haemodynamic effects during exercise seem not to have been examined. Therefore, an investigation of the haemodynamic effects of therapeutic doses of verapamil in man at rest and during exercise has been carried out.
negative inotropism.
Methods A single lumen Teflon catheter was introduced percutaneously into the ascending aorta and a double lumen catheter was positioned with its tip in the pulmonary artery, or in the wedged position. All pressures were recorded with a strain-gauge manometer (Bell-Howell). The catheter-manometer system had a straight frequency response up to about 15 Hz. The filter for the pressure signal was a low-pass one at iOO Hz, and the measuring system had a linearity better than one per cent. Static pressure calibration was done regularly. Electrocardiogram and pressure signals were processed with optional filtration, derivation and integration of the signals, which then were recorded by an ultraviolet recorder (Oscillofil, Siemens). Mean pressure values were obtained by electronic averaging with a one second time constant. To obtain dp/dt for the aortic pressure, a time constant of O.01 was used with low-pass filtration of that signal at IOO Hz. All signals were also recorded on a 4-channel analogue tape
318 recorder (Tandberg, Mod. i00) and later analysed on an IBM 18OO computer. The program used was developed by the Department of Aviation and Naval Medicine (Blomqvist et al., ]972). It enabled pressures in the aorta, pulmonary artery, pulmonary capillary venous pressure (PCV), pre-ejection period (PEP) and left ventricular ejection time (LVET), the maximal dp/dt of the aortic pressure and the systemic vascular resistance (SPR), left ventricular work (LVW), stroke work (SW), stroke pressure (SP) and tension-time (TTI) to be generated. Cardiac output was determined according to Fick. Exercise was performed in the supine position on an electrodynamically braked bicycle (Siemens-Elema). Statistical significance was assessed by the paired t-test.
Table i. Details of the subjects studied Subj. Age Height no. years cm
Weight kg
Heart vol. W]70 ml kpm/min
I
51
174
95
1085
1050
2
55
186
93
1065
1500
3
50
176
82
935
Ii00
4
49
176
80
855
1150
5
55
175
74
1085
1150
6
52
179
85
940
Ii00
7
44
188
80
635
1050
8
59
188
i01
1025
1300
I R
E C U M B E N T I R E S T I EXERCISE I Jfeet on bicycle pedals J
Subjects Eight subjectively healthy taxi-drivers participated in the study. The subjects were volunteers and they all received detailed verbal and written information concerning the purposes, procedures and risks of the planned catheterization and trial. They were in no way dependent upon the authors through employment, treatment or in any other way ] . Their mean age was 52 years, height 180 cm and body weight 86 kg (Table i). None had a history or any sign of heart disease. Every subject had performed an exercise test in the sitting position with stepwise increase in load, to obtain the load giving a heart rate of 170 beats/min (WITO) (SjSstrand, 1947; Wahlund, 1948), whilst a full ECG was recorded. In relation to total haemoglobin the work capacity was ordinary or good in all the subjects, and in relation to heart volume it was within the normal range (Ekelund,1972). One subject had ST-T changes during exercise that raised a suspicion of coronary insufficiency, and five subjects had ST-segment depression judged probably to be non-pathological. In relation to total haemoglobin three subjects had a heart volume larger than i S.D., and three subjects larger than 2 S.D. from the mean of a normal population.
Procedure The subjects stayed in the supine position both at rest and during exercise. The investigation procedure (Fig. i) consisted of two identical parts separated by a rest period of 90 minutes. During both parts of the investigation verapamil or placebo was given in a double-blind crossover fashion, according to the following scheme: verapamil was injected in a dose of 0.i mg/kg body weight, mean 8.6 mg in 2 min, followed by an infusion of 0.007 mg/kg per min (Table 2), or ] The study was approved by the Ethical Committee of the Karolinska Institute
~O
min
15
I
Io I
~;::+:+:!+~:.:.:.:+~.-'~;+++i+++~+~i++++:++'N+'+++i ~++++++~+++++:~++:+{~:++++
injection 8,6 mg • Pressure recording O Cardiac output acc. to Fick Fig. I. Schedule of investigation procedure
placobo was given. Cardiac output and blood pressure were measured during the 15 min rest period. Then the feet were placed on the bicycle pedals, which were located about 20 cm above the table, the next pressure recording was made, and exercise started immediately afterwards. The work load averaged 650 kpm/min (Table 2). In one subject the load was only about 100 kpm/min, due to a technical error. In the middle and at the end of the exercise period, cardiac output and blood pressures were again determined. The total exercise time averaged 14.9 min. The mean total amount of verapamil received by each volunteer was 21.4 mg (Table 2).
Results Basal Values The relationship between cardiac output and oxygen uptake at rest and during exercise was normal in all subjects, according to their age (Strandell, 1964). At rest one subject (no. 3) had an aortic diastolic blood pressure which was more than 2 S. D. above the normal mean in relation to cardiac output (Table 2). Subject 6 had a high diastolic
3]9 Table 2. Dose of v e r a p a m i l , w o r k load and duration, c a r d i a c output a o r t i c p r e s s u r e d u r i n g " p l a c e b o " - e x e r c i s e at 12-15 min.
Subj. Inital Total Work Work no. V e r a p a m i l V e r a p a m i l load duration dose dose mg mg kpm/min min
(CO), stroke v o l u m e
PA p r e s s u r e m m Hg systol, diastol, rest.
exer.
rest.
exer.
(SV), p u l m o n a r y a r t e r y
Aortic pressure rmn Hg systol, diastol, rest.
(PA) and
CO i/min
exer.
rest.
exer.
rest.
SV ml exer.
rest.
exer.
1
9.5
24.8
650
15.3
28
54
15
26
118
180
74
86
5.4
17.3
79
137
2
9.3
22.3
850
14.5
26
48
II
22
144
155
81
51
5.3
18.9
112
143
3
8.2
19.1
750
14.0
20
32
8
13
150
168
93
95
5.9
14.2
107
120
4
8.0
20.3
700
15.5
24
32
12
17
136
179
82
87
6.5
15.5
92
124
5
7.4
17.O
I00
15.5
19
24
7
II
125
128
76
76
6.9
7.8
118
114
6
8.5
21.7
700
14.7
30
48
17
25
III
173
70
80
6.2
16.6
91
125
7
8.0
18.6
750
14.3
18
33
8
I0
104
164
70
82
6.3
15.4
93
109
8
i0.I
27.0
750
15.5
21
36
I0
15
116
151
76
84
8.5
19.3
118
147
Table 3. Heart rate, aortic pressure, pulmonary capillary venous (PCV) pressure, pulmonary artery (PA) pressure and right ventricular (RV) pressure at rest and on exercise, during placebo and verapamil administration. P Heart rate beats/min
Placebo Verapamil Difference ~ign. rest exercise 4-7 min " 12-15 "
63 116 121
72 117 125
9 i 4
0.01
rest exercise 4-7 " " 12-15 "
126 168 162
116 161 156
-IO - 7 - 6
0.05 0.i0 0.05
rest exercise 4-7 " " 12-15 "
99 118 109
94 116 112
- 5 - 2 3
0.05
rest exercise 4-7 " " 12-15 "
78 86 80
74 86 82
- 4 O 2
0.05
rest exercise 4-7 " " 12-15 "
10.5 24.1 16.3
12.4 22.1 17.4
1.9 - 2.0 I.I
0.01
PA pressure rest mm Hg exercise 4-7 " systolic " 12-15 "
26 43 38
27 42 37
1 1 1
0.I0
rest exercise 4-7 " " 12-15 "
18 31 27
20 31 27
2 0 0
0.01
rest exercise 4-7 " " 12-15 "
13 21 17
14 20 18
1 I 1
0.001
RV pressure rest mm Hg exercise 4-7 " systolic " 12-15 "
27 47 43
28 47 45
end diastolic rest exercise 4-7 " " 12-15 "
10.3 11.6 9.6
10.8 12.9 10.4
Aortic pressure m Hg systolic mean
diastolic
PCV mean mm Hg
diastolic
0.O01
Table 4. Cardiac output, stroke volume, systemic vascular resistance, pulmonary vascu]ar resistance, atrioventricular conduction time (PQ), pre-ejection period (PEP), left ventricular ejection time (LVET),max dp/dt aortic pressure, left ventricular work (LVW), stroke work (SW), tension-time index at rest and on exercise, during placebo and verapamil administration. Placebo Verapamil Difference sign. p< Cardiac output I/min
exercise 4-7 min " 12-15 "
Stroke volume ml
exercise 4-7 " " 12-15 '~
129 127
127 125
- 2 - 2
Systemic vascular resistance ioS(Ns/m 5)
exercise 4-7 " " 12-15 "
580 590
578 538
- 2 -52
Pulmonary vascular resistance 105(Ns/m 5)
exercise 4-7 " " 12-15 "
38.1 48.3
49.7 46.5
11.6 - 1.8
rest exercise 4-7 " " 12-15 "
16.2 14.4 14.3
17.1 15.2 14.8
0.9 0.8 0.5
0.05 0.i0 0.I0
PEP rest HiR corrected exercise 4-7 " csec " 12-15 "
17.6
16.8
- 0.8
0.01
14.4 14.5
14.5 14.8
0. I 0.3
LVET rest HR corrected exercise ~-7 " csec " 12-15 "
41.2
39.7
- 1.5
45.5 44.8
45.0 44.8
- 0.5
PQ time csec
15.3 15.6
15.1 15.7
- 0.2 O.i
max. dp/dt aortic pressure mm Hgs
exercise 4-7 " " 12-15 "
LVW watt
exercise 4-7 " " 12-15 "
3.54 3.97
3.48 3.80
- 0.06 - O.17
SW joule
exercise 4-7 " " 12-15 "
1.87 2.02
1.78 1.83
- 0.09 - 0.19
TTI nml Hg.s.HR
rest exercise 4-7 "
rest
650
670
20
1460 1500
1420 1540
-40 40
0.05
0,01
0.5 1.3 0.8
"
2300 3810 3710
2340 4080 3650
40 27 -60
0.05
320 pulmonary artery pressure at rest in relation to cardiac output. During exercise subjects 1 and 4 developed an increased systolic aortic blood pressure, and another (no. 3) continued to have a diastolic aortic pressure outside the normal limits. One subject (no. I) had a systolic pulmonary artery pressure of up to 67 mm Hg during exercise, and a further four had high systolic and/or diastolic pulmonary artery pressures. Three of the subjects reached their highest value during "placebo" exercise preceding "Verapamil" exercise. The normal limits mentioned above were taken from a study by Ekelund and Holmgren (1967). Effect of Verapamil
Rest. After injection of verapamil the heart rate rose on average by 9 beats/min (Table 3). The aortic blood pressure decreased by 10,5 and 4 mm Hg systolic, mean and diastolic values, respectively. The maximal aortic dp/dt was unchanged (Table 4). The PCV mean pressure rose by 1.9 mm Hg at rest, the mean pulmonary artery pressure by 2 mm Hg, and diastolic pressure by 1 mm Hg (Table 3). Right ventricular systolic pressure increased by 1 mm Hg on average. All the changes were statistically significant. No significant change occurred in right ventricular end diastolic pressure. The atrioventricular conduction time was significantly prolonged, on average by 0.9 cs (range -0.2-+3.5), the longest individual PQ time being 19 cs (Table 4). The pre-ejection period was shortened significantly, by Ii ms, and the difference persisted after heart rate correction according to Weissler et a/.(1972). Left ventricular ejection time did not differ between the two periods of rest. There was no change in the tension-time index.
Exercise. During exercise, too, there was a higher heart rate and lower systolic aortic pres ~ sure after verapamil (Table 3). After 15 minutes of exercise, the difference in relation to placebo was 4 beats/min and 6 mm Hg, respectively. The increased pressures in the pulmonary circulation caused by verapamil at rest disappeared during exercise. Cardiac output and stroke volume did not differ from the values found in placebo exercise (Table 4). Systemic vascular resistance diminished by I0 per cent. There was no change in pulmonary vascular resistance after verapamil. Left ventricular work and stroke work diminished during verapamil administration, but the difference in relation to placebo was significant only for stroke work. The tension-time index did not change between the two periods. The PQ time was prolonged during exercise by verapamil. The preejection period was not significantly changed. Left ventricular ejection time was shorter after verapamil, but not after correction for heart rate.
Discussion The subjects chosen for the study were middleaged, as that is the usual age when treatment with
verapamil is commenced. They were subjectively healthy, but some had increased blood pressures in the systemic or pulmonary circulations at rest, and/or during exercise. This should accentuate the haemodynamic effects of verapamil. At rest, the arterial blood pressure fell after administration of verapamil, a result in agreement with other investigations in man and animals (Brittinger et al., 1970; Ross and Jorgensen, 1968; Ryd~n and Saetre, 1971). A fall in blood pressure has been described previously (Haas and Hgrtfelder, 1962; Ross and Jorgensen, 1967) and is the result of a decrease in systemic vascular resistance. The slightly negative inotropic effect on the heart, evidenced by an increase in pulmonary pressure, might contribute, too, as it has been shown to do in animal experiments, The preejection period was shorter, which indicates that the negative inotropic effect of verapamil is slight in vivo, and indirectly it may be deduced that the effect on left ventricular contractility is also slight (Perloff and Reichek, 1972). The maximal aortic dp/dt, another expression of left ventricular contractility, was unchanged during verapamil administration, which also indicates that any negative inotropic effect was slight. This is in agreement with the experience of others both in clinical and laboratory practice (Ryd~n and Saetre, 1971; Bass and Friedemann, 1971). The pressure increase in the pulmonary circulation seen at rest was not apparent during exercise after dosing with verapamil; nor were the other variables which are influenced by ventricular contractility (cardiac output/volume and maximal dp/dt aortic pressure) altered by verapamil plus exercise. The positive inotropic effect produced during exercise by increased sympathetic activity surpassed the slight negative inotropic effect of verapamil, even though half the subjects had abnormally raised pressures during "placebo" exercise. In such subjects it might be expected that the negative inotropic properties of a drug would be accentuated by a load, such as exercise. These results confirm studies both in animals and human, which indicate that verapamil does not have any beta-receptor blocking activity (Bass and Friedemann, 1971; Benfey et al., 1967~ Nayler and Szeto, 1972; Ross and Jorgensen, 1967). In anaesthetised animals verapamil may directly depress the activity of the sinus node (Garvey, 1969; Ross and Jorgensen, 1967), which results in bradycardia (Melville et al., 1968; Nayler et al., 1968). However, the pulse rate increased in this study in conscious men with normal heart rates at rest, in accordance with previous reports (Bass and Friedemann, 1971; Brittinger et al., 1970; Ryd~n and Saetre, 1971). The increase in heart rate may be regarded as a reflex effect following the fall in systemic blood pressure, and indicates that the reflex response was not blocked by a direct action on the sinus node. The prolongation of PQ time, despite a higher heart rate was also in agreement with earlier studies, and indicates that verapamil had more activity on the atrioventricular node than on the sinus node.
321 In addition to its antiarrhythmic activity, verapamil may also be prescribed for patients suffering from angina pectoris in order to increase their physical work capacity (AtterhSg and Porj~, 1966~ Sandler et al., 1968). This use makes those variables which are susceptible to left ventricular oxygen demand of special interest. However, the tension-time index did not differ significantly from the result in the placebo period, and although both left ventricular work and stroke work were lower, only the latter had fallen significantly. The results show that verapamil prolonged the PQ interval at rest, as well as with a strong tendency to do so during exercise (p
(1975)
Haemodynamic Effects of Intravenous Verapamil at Rest and during Exercise in Subjectively Healthy Middle-Aged Men J.-H. AtterhSg and L.-G. Ekelund Department
of Clinical Physiology,
Received: May 7, 1974,
accepted:
Karolinska Sjukhuset,
Stockholm,
Sweden
January ii, 1975
Summary, Verapamil, 0.I mg/kg body wt, was injected i.v. over 2 minutes in 8 subjectively healthy middle-aged men, followed by a continuous infusion of 0.007 mg/kg body wt per minute. Prior to the injection several of the subjects had raised pulmonary or systemic arterial pressures. At rest, the central pressures increased slightly, which was taken as a sign of a moderate negative inotropic effect, but there was no change in pre-ejection period or maximal dp/dt of the aortic pressure. The heart rate increased and there was a small decrease in systemic arterial pressure, probably due to a fall of systemic vascular resistance. The PQ time was prolonged. During exercise, with its positive inotropic stimulation, the moderate negative inotropic effect of verapamil disappeared, whereas the increase in heart rate and decrease in aortic pressures persisted. Some variables that reflected the oxygen demand of the heart decreased. The slight negative inotropic effect does not appear to be a particular contraindication to the use of verapamil, but it should be employed cautiously in conditions with a compensatory rise in systemic vascular resistance, or if atrioventricular conduction is impaired, Key words: Verapamil, haemodynamics,
exercise, man, vascular resistance,
In the past ten years interest has grown rapidly in compounds with a new mode of action, namely those which antagonise calcium effects in vascular smooth muscle and the heart, of which verapamil (Fleckenstein et al., 1967) is a well-known example. The indications for verapamil have steadily increased to its present extensive use (AtterhSg, 1969; Bender et al., 1966; Brittinger et al., 1970; Karnell and KShler, 1971; Schamroth et al., 1972). From clinical experience and a small number of haemodynamic investigations it is known that verapamil may have negative dromotropic, chronotropic and inotropic effects (Fleckenstein et al., 1967; Haas and H~rtfelder, 1962; Nayler et al., 1968; Ryd~n and Saetre, 1971; Schamroth, 1971; Singh and Vaugham Williams, 1972). However, studies in man at rest have been few and in part controversial and the haemodynamic effects during exercise seem not to have been examined. Therefore, an investigation of the haemodynamic effects of therapeutic doses of verapamil in man at rest and during exercise has been carried out.
negative inotropism.
Methods A single lumen Teflon catheter was introduced percutaneously into the ascending aorta and a double lumen catheter was positioned with its tip in the pulmonary artery, or in the wedged position. All pressures were recorded with a strain-gauge manometer (Bell-Howell). The catheter-manometer system had a straight frequency response up to about 15 Hz. The filter for the pressure signal was a low-pass one at iOO Hz, and the measuring system had a linearity better than one per cent. Static pressure calibration was done regularly. Electrocardiogram and pressure signals were processed with optional filtration, derivation and integration of the signals, which then were recorded by an ultraviolet recorder (Oscillofil, Siemens). Mean pressure values were obtained by electronic averaging with a one second time constant. To obtain dp/dt for the aortic pressure, a time constant of O.01 was used with low-pass filtration of that signal at IOO Hz. All signals were also recorded on a 4-channel analogue tape
318 recorder (Tandberg, Mod. i00) and later analysed on an IBM 18OO computer. The program used was developed by the Department of Aviation and Naval Medicine (Blomqvist et al., ]972). It enabled pressures in the aorta, pulmonary artery, pulmonary capillary venous pressure (PCV), pre-ejection period (PEP) and left ventricular ejection time (LVET), the maximal dp/dt of the aortic pressure and the systemic vascular resistance (SPR), left ventricular work (LVW), stroke work (SW), stroke pressure (SP) and tension-time (TTI) to be generated. Cardiac output was determined according to Fick. Exercise was performed in the supine position on an electrodynamically braked bicycle (Siemens-Elema). Statistical significance was assessed by the paired t-test.
Table i. Details of the subjects studied Subj. Age Height no. years cm
Weight kg
Heart vol. W]70 ml kpm/min
I
51
174
95
1085
1050
2
55
186
93
1065
1500
3
50
176
82
935
Ii00
4
49
176
80
855
1150
5
55
175
74
1085
1150
6
52
179
85
940
Ii00
7
44
188
80
635
1050
8
59
188
i01
1025
1300
I R
E C U M B E N T I R E S T I EXERCISE I Jfeet on bicycle pedals J
Subjects Eight subjectively healthy taxi-drivers participated in the study. The subjects were volunteers and they all received detailed verbal and written information concerning the purposes, procedures and risks of the planned catheterization and trial. They were in no way dependent upon the authors through employment, treatment or in any other way ] . Their mean age was 52 years, height 180 cm and body weight 86 kg (Table i). None had a history or any sign of heart disease. Every subject had performed an exercise test in the sitting position with stepwise increase in load, to obtain the load giving a heart rate of 170 beats/min (WITO) (SjSstrand, 1947; Wahlund, 1948), whilst a full ECG was recorded. In relation to total haemoglobin the work capacity was ordinary or good in all the subjects, and in relation to heart volume it was within the normal range (Ekelund,1972). One subject had ST-T changes during exercise that raised a suspicion of coronary insufficiency, and five subjects had ST-segment depression judged probably to be non-pathological. In relation to total haemoglobin three subjects had a heart volume larger than i S.D., and three subjects larger than 2 S.D. from the mean of a normal population.
Procedure The subjects stayed in the supine position both at rest and during exercise. The investigation procedure (Fig. i) consisted of two identical parts separated by a rest period of 90 minutes. During both parts of the investigation verapamil or placebo was given in a double-blind crossover fashion, according to the following scheme: verapamil was injected in a dose of 0.i mg/kg body weight, mean 8.6 mg in 2 min, followed by an infusion of 0.007 mg/kg per min (Table 2), or ] The study was approved by the Ethical Committee of the Karolinska Institute
~O
min
15
I
Io I
~;::+:+:!+~:.:.:.:+~.-'~;+++i+++~+~i++++:++'N+'+++i ~++++++~+++++:~++:+{~:++++
injection 8,6 mg • Pressure recording O Cardiac output acc. to Fick Fig. I. Schedule of investigation procedure
placobo was given. Cardiac output and blood pressure were measured during the 15 min rest period. Then the feet were placed on the bicycle pedals, which were located about 20 cm above the table, the next pressure recording was made, and exercise started immediately afterwards. The work load averaged 650 kpm/min (Table 2). In one subject the load was only about 100 kpm/min, due to a technical error. In the middle and at the end of the exercise period, cardiac output and blood pressures were again determined. The total exercise time averaged 14.9 min. The mean total amount of verapamil received by each volunteer was 21.4 mg (Table 2).
Results Basal Values The relationship between cardiac output and oxygen uptake at rest and during exercise was normal in all subjects, according to their age (Strandell, 1964). At rest one subject (no. 3) had an aortic diastolic blood pressure which was more than 2 S. D. above the normal mean in relation to cardiac output (Table 2). Subject 6 had a high diastolic
3]9 Table 2. Dose of v e r a p a m i l , w o r k load and duration, c a r d i a c output a o r t i c p r e s s u r e d u r i n g " p l a c e b o " - e x e r c i s e at 12-15 min.
Subj. Inital Total Work Work no. V e r a p a m i l V e r a p a m i l load duration dose dose mg mg kpm/min min
(CO), stroke v o l u m e
PA p r e s s u r e m m Hg systol, diastol, rest.
exer.
rest.
exer.
(SV), p u l m o n a r y a r t e r y
Aortic pressure rmn Hg systol, diastol, rest.
(PA) and
CO i/min
exer.
rest.
exer.
rest.
SV ml exer.
rest.
exer.
1
9.5
24.8
650
15.3
28
54
15
26
118
180
74
86
5.4
17.3
79
137
2
9.3
22.3
850
14.5
26
48
II
22
144
155
81
51
5.3
18.9
112
143
3
8.2
19.1
750
14.0
20
32
8
13
150
168
93
95
5.9
14.2
107
120
4
8.0
20.3
700
15.5
24
32
12
17
136
179
82
87
6.5
15.5
92
124
5
7.4
17.O
I00
15.5
19
24
7
II
125
128
76
76
6.9
7.8
118
114
6
8.5
21.7
700
14.7
30
48
17
25
III
173
70
80
6.2
16.6
91
125
7
8.0
18.6
750
14.3
18
33
8
I0
104
164
70
82
6.3
15.4
93
109
8
i0.I
27.0
750
15.5
21
36
I0
15
116
151
76
84
8.5
19.3
118
147
Table 3. Heart rate, aortic pressure, pulmonary capillary venous (PCV) pressure, pulmonary artery (PA) pressure and right ventricular (RV) pressure at rest and on exercise, during placebo and verapamil administration. P Heart rate beats/min
Placebo Verapamil Difference ~ign. rest exercise 4-7 min " 12-15 "
63 116 121
72 117 125
9 i 4
0.01
rest exercise 4-7 " " 12-15 "
126 168 162
116 161 156
-IO - 7 - 6
0.05 0.i0 0.05
rest exercise 4-7 " " 12-15 "
99 118 109
94 116 112
- 5 - 2 3
0.05
rest exercise 4-7 " " 12-15 "
78 86 80
74 86 82
- 4 O 2
0.05
rest exercise 4-7 " " 12-15 "
10.5 24.1 16.3
12.4 22.1 17.4
1.9 - 2.0 I.I
0.01
PA pressure rest mm Hg exercise 4-7 " systolic " 12-15 "
26 43 38
27 42 37
1 1 1
0.I0
rest exercise 4-7 " " 12-15 "
18 31 27
20 31 27
2 0 0
0.01
rest exercise 4-7 " " 12-15 "
13 21 17
14 20 18
1 I 1
0.001
RV pressure rest mm Hg exercise 4-7 " systolic " 12-15 "
27 47 43
28 47 45
end diastolic rest exercise 4-7 " " 12-15 "
10.3 11.6 9.6
10.8 12.9 10.4
Aortic pressure m Hg systolic mean
diastolic
PCV mean mm Hg
diastolic
0.O01
Table 4. Cardiac output, stroke volume, systemic vascular resistance, pulmonary vascu]ar resistance, atrioventricular conduction time (PQ), pre-ejection period (PEP), left ventricular ejection time (LVET),max dp/dt aortic pressure, left ventricular work (LVW), stroke work (SW), tension-time index at rest and on exercise, during placebo and verapamil administration. Placebo Verapamil Difference sign. p< Cardiac output I/min
exercise 4-7 min " 12-15 "
Stroke volume ml
exercise 4-7 " " 12-15 '~
129 127
127 125
- 2 - 2
Systemic vascular resistance ioS(Ns/m 5)
exercise 4-7 " " 12-15 "
580 590
578 538
- 2 -52
Pulmonary vascular resistance 105(Ns/m 5)
exercise 4-7 " " 12-15 "
38.1 48.3
49.7 46.5
11.6 - 1.8
rest exercise 4-7 " " 12-15 "
16.2 14.4 14.3
17.1 15.2 14.8
0.9 0.8 0.5
0.05 0.i0 0.I0
PEP rest HiR corrected exercise 4-7 " csec " 12-15 "
17.6
16.8
- 0.8
0.01
14.4 14.5
14.5 14.8
0. I 0.3
LVET rest HR corrected exercise ~-7 " csec " 12-15 "
41.2
39.7
- 1.5
45.5 44.8
45.0 44.8
- 0.5
PQ time csec
15.3 15.6
15.1 15.7
- 0.2 O.i
max. dp/dt aortic pressure mm Hgs
exercise 4-7 " " 12-15 "
LVW watt
exercise 4-7 " " 12-15 "
3.54 3.97
3.48 3.80
- 0.06 - O.17
SW joule
exercise 4-7 " " 12-15 "
1.87 2.02
1.78 1.83
- 0.09 - 0.19
TTI nml Hg.s.HR
rest exercise 4-7 "
rest
650
670
20
1460 1500
1420 1540
-40 40
0.05
0,01
0.5 1.3 0.8
"
2300 3810 3710
2340 4080 3650
40 27 -60
0.05
320 pulmonary artery pressure at rest in relation to cardiac output. During exercise subjects 1 and 4 developed an increased systolic aortic blood pressure, and another (no. 3) continued to have a diastolic aortic pressure outside the normal limits. One subject (no. I) had a systolic pulmonary artery pressure of up to 67 mm Hg during exercise, and a further four had high systolic and/or diastolic pulmonary artery pressures. Three of the subjects reached their highest value during "placebo" exercise preceding "Verapamil" exercise. The normal limits mentioned above were taken from a study by Ekelund and Holmgren (1967). Effect of Verapamil
Rest. After injection of verapamil the heart rate rose on average by 9 beats/min (Table 3). The aortic blood pressure decreased by 10,5 and 4 mm Hg systolic, mean and diastolic values, respectively. The maximal aortic dp/dt was unchanged (Table 4). The PCV mean pressure rose by 1.9 mm Hg at rest, the mean pulmonary artery pressure by 2 mm Hg, and diastolic pressure by 1 mm Hg (Table 3). Right ventricular systolic pressure increased by 1 mm Hg on average. All the changes were statistically significant. No significant change occurred in right ventricular end diastolic pressure. The atrioventricular conduction time was significantly prolonged, on average by 0.9 cs (range -0.2-+3.5), the longest individual PQ time being 19 cs (Table 4). The pre-ejection period was shortened significantly, by Ii ms, and the difference persisted after heart rate correction according to Weissler et a/.(1972). Left ventricular ejection time did not differ between the two periods of rest. There was no change in the tension-time index.
Exercise. During exercise, too, there was a higher heart rate and lower systolic aortic pres ~ sure after verapamil (Table 3). After 15 minutes of exercise, the difference in relation to placebo was 4 beats/min and 6 mm Hg, respectively. The increased pressures in the pulmonary circulation caused by verapamil at rest disappeared during exercise. Cardiac output and stroke volume did not differ from the values found in placebo exercise (Table 4). Systemic vascular resistance diminished by I0 per cent. There was no change in pulmonary vascular resistance after verapamil. Left ventricular work and stroke work diminished during verapamil administration, but the difference in relation to placebo was significant only for stroke work. The tension-time index did not change between the two periods. The PQ time was prolonged during exercise by verapamil. The preejection period was not significantly changed. Left ventricular ejection time was shorter after verapamil, but not after correction for heart rate.
Discussion The subjects chosen for the study were middleaged, as that is the usual age when treatment with
verapamil is commenced. They were subjectively healthy, but some had increased blood pressures in the systemic or pulmonary circulations at rest, and/or during exercise. This should accentuate the haemodynamic effects of verapamil. At rest, the arterial blood pressure fell after administration of verapamil, a result in agreement with other investigations in man and animals (Brittinger et al., 1970; Ross and Jorgensen, 1968; Ryd~n and Saetre, 1971). A fall in blood pressure has been described previously (Haas and Hgrtfelder, 1962; Ross and Jorgensen, 1967) and is the result of a decrease in systemic vascular resistance. The slightly negative inotropic effect on the heart, evidenced by an increase in pulmonary pressure, might contribute, too, as it has been shown to do in animal experiments, The preejection period was shorter, which indicates that the negative inotropic effect of verapamil is slight in vivo, and indirectly it may be deduced that the effect on left ventricular contractility is also slight (Perloff and Reichek, 1972). The maximal aortic dp/dt, another expression of left ventricular contractility, was unchanged during verapamil administration, which also indicates that any negative inotropic effect was slight. This is in agreement with the experience of others both in clinical and laboratory practice (Ryd~n and Saetre, 1971; Bass and Friedemann, 1971). The pressure increase in the pulmonary circulation seen at rest was not apparent during exercise after dosing with verapamil; nor were the other variables which are influenced by ventricular contractility (cardiac output/volume and maximal dp/dt aortic pressure) altered by verapamil plus exercise. The positive inotropic effect produced during exercise by increased sympathetic activity surpassed the slight negative inotropic effect of verapamil, even though half the subjects had abnormally raised pressures during "placebo" exercise. In such subjects it might be expected that the negative inotropic properties of a drug would be accentuated by a load, such as exercise. These results confirm studies both in animals and human, which indicate that verapamil does not have any beta-receptor blocking activity (Bass and Friedemann, 1971; Benfey et al., 1967~ Nayler and Szeto, 1972; Ross and Jorgensen, 1967). In anaesthetised animals verapamil may directly depress the activity of the sinus node (Garvey, 1969; Ross and Jorgensen, 1967), which results in bradycardia (Melville et al., 1968; Nayler et al., 1968). However, the pulse rate increased in this study in conscious men with normal heart rates at rest, in accordance with previous reports (Bass and Friedemann, 1971; Brittinger et al., 1970; Ryd~n and Saetre, 1971). The increase in heart rate may be regarded as a reflex effect following the fall in systemic blood pressure, and indicates that the reflex response was not blocked by a direct action on the sinus node. The prolongation of PQ time, despite a higher heart rate was also in agreement with earlier studies, and indicates that verapamil had more activity on the atrioventricular node than on the sinus node.
321 In addition to its antiarrhythmic activity, verapamil may also be prescribed for patients suffering from angina pectoris in order to increase their physical work capacity (AtterhSg and Porj~, 1966~ Sandler et al., 1968). This use makes those variables which are susceptible to left ventricular oxygen demand of special interest. However, the tension-time index did not differ significantly from the result in the placebo period, and although both left ventricular work and stroke work were lower, only the latter had fallen significantly. The results show that verapamil prolonged the PQ interval at rest, as well as with a strong tendency to do so during exercise (p
