Comparison of Atenolol,
of the Subacute
Hemodynamic
Propranolol, Pindolol,
Effects
and Nebivolol
M.D., F.I.C.A. Carlos Cobo, M.D.
Jean De Crée,
Geukens and
Hedwig Herman
Verhaegen, M.D., Ph.D.,
F.I.C.A.
MERKSEM, BELGIUM
Abstract In an observer-blind four-way crossover study, 7 healthy volunteers received in random sequence, one month apart, atenolol 100 mg od, propranolol (slow release) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od for a period of seven days, followed by a single-blind placebo washout period of seven days. The decrease of peak exercise heart rate and systolic blood pressure was significant 0.02) and comparable for the four drugs studied and varied between 15% (p and 23% for heart rate and between 15% and 20% for systolic blood pressure. Although no statistically significant difference was observed among the four drug regimens, the decrease of peak exercise heart rate was less pronounced with nebivolol than with the three reference beta-blocking agents. The ratio of the preejection period (PEP ), an c ) to the left ventricular ejection time (LVET c indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. c /LVET PEP with nebivolol from a control value of and significantly improved progressively 0.37 ± 0.012 to 0.31 ± 0.009 (p = 0.03) after seven days of treatment, owing to a decrease in PEP c and an increase in LVET , suggestive of a combined effect c both on preload and afterload. Postexercise LVET , an index of the intrinsic c positive inotropy of exercise, was significantly suppressed by atenolol, propranolol, and pindolol, but not during treating with nebivolol. These data suggest that nebivolol is a β1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular com=
pliance.
From the Clinical Research Unit St. Bartholomeus, Jan
Palfijn Hospital, Merksem, Belgium
95
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96 Introduction
;.
.
:
:
.
. ; :r
Nebivolol is a chemically novel J3-adrenergic antagonist.’ In vitro nebivolol has been found to be a potent antagonist of J31-adrenergic receptors with greater selectivity for the J31-adrenergic receptor than any of the reference compounds has.’ Nebivolol has an unusual combination of pharmacologic properties. In closed-chest anesthetized dogs, besides the @-blocking properties, nebivolol at low dose slightly decreased systemic vascular resistance and increased stroke volume and cardiac output. In contrast to classical J3-adrenergic antagonists, nebivolol acutely I lowers systolic and diastolic blood pressure in spontaneously hypertensive rats.’ In man, nebivolol significantly attenuates exercise heart rate and systolic blood pressure after acute and subacute oral treatment; improves left ventricular performance at rest, as measured with systolic time intervals and with equilibrium radionucline angiocardiography, and keeps the intrinsic positive inotropy of exercise unaffected during prolonged treatment . 2-4 In hypertensive patients nebivolol significantly decreases systolic and diastolic blood pressure for a substantial 1 period of time after a single oral dose.’ The present study was conducted to assess the subacute hemodynamic profile of nebivolol in human volunteers in comparison with those of three classical J3-adrenergic antagonists.
..
~
Materials and Methods
:
>
. :
.,
.. -
Seven
apparently healthy volunteers, aged between twenty-five and forty-eight (median: thirty-six) years, participated in this study. Each subject gave his informed consent to the experimental procedure. The volunteers were requested not to change their personal habits of physical activity, alcohol ingestion, or tobacco consumption throughout the study. They were °
~ allowed to take any other medication. ’~= &dquo;-1’: °i&dquo;~-~~~.. Before and after exercise, observer-blind blood pressure measurements were assessed with an automated device, consisting of an inflatable cuff and an oscillatory detection system for systolic and diastolic blood pressure with all values registered on a built-in recorder. Blood pressure measurements were always done in supine position after a rest of ten minutes in a quiet room. During exercise systolic blood pressure measurements were done with a sphygmomanometer and a stethoscope always by the same observer at the left upper extremity. A standardized multistage exercise test of nine minutes’ duration was performed on a 5 treadmill, with adjustable speed and inclination, and by use of a modified protocol of Bruce.5 For the first three minutes the volunteers had to walk at a speed of 2.5 mph, at an inclination of 10%. For the next three minutes, speed was increased to 3.4 mph at an inclination of 12% and for the last three minutes to 4.2 mph at an inclination of 14%. Continuous ECG monitoring on an oscilloscope and recording of the peripheral leads and a precordial lead (V5) on a six-channel instrument allowed measurements of heart rate every minute during exercise and a recovery period up to six minutes after the end of exercise. Systolic blood pressure measurements were done every three minutes during exercise and at one, three, and six minutes during recovery. Systolic time intervals were measured from simultaneous recordings (at a paper speed of 100 mm/sec) of a peripheral lead of the ECG, phonocardiogram (pulse phonotransducer), and carotid pulse wave. Five to ten consecutive cardiac cycles were analyzed and averaged for the
not
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.
97
following parameters: Q$2, total electromechanical systole; LVET, left ventricular ejection time; PEP, preejection period. LVET, PEP and QS, were corrected for heart rate according to our resting supine regression equations~: LVETC = -1.2396 (72-HR) + LVET, PEP, = -0.4187 (72-HR) + PEP and QS2C = -1.7112 (72-HR) + QS2, which are similar to that of Weissler al.’ The ratio of the PEP,
to the LVETC (PEP./LVET,) was used as an index of left ventricular of An performance. analysis variance showed the residual variation to be negligible ( ± 3.5%) so that differences as small as 5% are representative for real changes of left ventricular
et
6
performance . The difference between a measure of the LVET, before exercise and thirty seconds after the end of exercise was also calculated and expressed as LVET,. For this purpose the postexercise regression equation LVETC = -0.7708 (72-HR) + LVET was used to correct for 6 heart rate. Statistical evaluation was calculated by means of the Wilcoxon matched-pairs, signed-ranks 8 test, two-tailed probability.~ Each subject received in random sequence and in a four-way crossover fashion one month apart for each session the following four beta-adrenergic antagonists for seven days, followed by a seven-day single-blind placebo period: atenolol 100 mg od, propranolol (slow-release formulation) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od. Study medication was always taken at breakfast and for pindolol additionally at noon and at 6 P M. All measurements were performed at exactly the same time of the day. Measurements of systolic time intervals at rest, systolic and diastolic blood pressure, and heart rate were done on a control day and before daily intake of the study medication, on days 1, 2, 3, 4, and 7 during p-blocker treatment and on days l, 2, and 7 during subsequent placebo treatment. An exercise test and the above-mentioned measurements at rest were also performed six hours after administration of atenolol, propranolol, and nebivolol and three hours after administration of pindolol on a control day, on days 1, 4, and 7 during (3-blocker treatment and on days l, 2, and 7 during subsequent placebo treatment. Since it was impossible to administer all drugs in identical form, we instructed an independent observer (a pharmacist of our department) to distribute the study medication to the volunteers. In order to keep the experiment observer-blind, the volunteers were requested to exchange no information about their medication to the observers. .
Results No significant differences were observed during the baseline examinations during the four different sessions. The results for heart rate and systemic blood pressure at rest, for exercise heart rate and systolic blood pressure, and for systolic time intervals at rest and after exercise were comparable and not significantly different at baseline evaluation for the four different sessions in these 7 volunteers (Tables I, II, and III, Figures 1 and 3). The results of the exercise-induced changes of heart rate and systolic blood pressure during the administration of the different J3-adrenergic antagonists are summarized in Table I. The increases of heart rate and systolic blood pressure during exercise and during recovery were significantly inhibited (p = 0.02) from the first day of treatment and during the seven days of treatment with the four study medications. At peak exercise mean heart rate decreased from a control value of 156 beats/min ± 1.4 to 120 ± 4.0 on the seventh day of treatment with
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98 5.6 to 125 :i: 4.0 during treatment with propranolol, from 162 beats/min z- 4.6 to 127 ± 3.2 with pindolol, and from 154 beats/min ± 6.6 to 131 ± 4.9 with nebivolol. Mean maximal systolic blood pressure was reduced from a control value of 164 mmHg ± 4.7 to 121 ± 5.5 on the seventh day of treatment with atenolol, from 163 mmHg ± 11.9 to 134 ± 7.8 during treatment with propranolol, from 159 mmHg ± 4.1 to 136 ± 5.3 with pindolol, and from 164 mmHg ± 7.2 to 136 ± 8.8 with nebivolol. After discontinuation of treatment, exercise heart rate remained significantly reduced for up to two days after the last dose of atenolol, propranolol, and nebivolol, but with pindolol the effects on exercise heart rate were not significantly different from control values from twenty-four hours after the last dose. Exercise systolic blood pressure remained significantly different for up to two days after discontinuation of treatment with atenolol and nebivolol, whereas with propranolol and pindolol no such differences were observed from twenty-four hours after the last dose (Table I).
atenolol, from 159 beats/min
.
~-
TABLE I Metiti Values ::t SE of
Test
on all
Ma.rinral Heart Rate
C olltrol Day.
on
(Beats/Min) (HR) and Systolic Blood Pressure (mmHg) (SBP) During an Exercise
Days l, 4, and 7 During Treatment and on Days 1, 2, and 7After Discontinuation ofTreatment Propranolol 160 mg od, Pindolol 5 ing tid, and Nebivolol 5 mg od in 7 Volunteers
with Atenolol 100 ing od,
p-values.
Wilcoxon
matched-paira signed-rank,,
test versus
control
day (2-tailed probability:
ns
=
not
significant)
values of heart rate and of systolic and diastolic blood pressure are given in Table II. At rest, heart rate decreased significantly during treatment with atenolol and propranolol but not during treatment with pindolol and nebivolol. Systolic blood pressure at rest decreased significantly from a starting value of 117 mmHg ± 2.6 to 110 ± 4.4 after seven days of treatment with atenolol, from 116 mmHg ± 2.8 to 1111 ± 4.0 with propranolol, and from 119 mmHg ± 2.4 to 101 ± 3.8 with nebivolol. Diastolic blood pressure at rest decreased significantly with nebivolol from a starting value of 72 mmHg ± 1.5 to 61 ± 2.5 after seven days of treatment. During treatment with pindolol systolic and diastolic blood pressure did not change significantly. The significant reduction of resting values of systolic and diastolic blood pressure during treatment with nebivolol lasted for two days after discontinuation of treatment
Resting
(Table II). The results of the different parameters of the systolic time intervals measured in the morning before daily administration of the study medication are shown in Table III and Figure 1. The ratio of the PEP./LVET, did not change significantly during treatment with atenolol, propranolol, and pindolol, except for a slight but significant lengthening of the LVET, on the seventh day during treatment with atenolol and propranolol and except for a significant increase of the QS2,’ during treatment with propranolol. In contrast, the ratio of the PEPc/LVETc progressively and significantly decreased during treatment with nebivolol from a starting value
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99 TABLE II Mean Values ± SE of Heart Rate and of Systolic and Diastolic Blood Pressure at Rest on a Control Duy, Befi>re Daily Administration on Days 1, 2, 3, 4, and 7 During Treatment and on Days /, 2, and 7 After Discontinuation of Treatment with Atenolol 100 mg od, Propranolol 160 mg od, Pindolol 5 mg tid, and Nebivolol 5 mg od in 7 Volunteers
*
p-values.
Wilcoxon
matched-pairs signed-ranks
test versus
day (2-tailed probability;
ns
=
not
significant)
of treatment. The decrease of the ratio PEP./LVET, was due to a significant shortening of the PEP, and a significant lengthening of the LVET,. Mean values of PEP, decreased from an initial value of 105 msec ± 4.3 to 96 ± 2.3 after seven days of treatment and mean values of LVET, increased from a control value of 286 msec ± 3.7 to 305 ± 2.4. These significant changes in Pep LVET,, and PEP./LVET, persisted for up to two days after discontinuation of treatment with nebivolol. The results of the systolic time intervals, measured in the afternoon six hours after daily intake of atenolol, propranolol, and nebivolol and three hours after intake of pindolol, are similar to those measured in the morning before daily administration of the study medication, except for a transient and significant decrease of the ratio PEP)LVETc observed only during the first day of treatment with pindolol (Figure 2). Mean values of the ratio PEP,/LVET, decreased from a control value of 0.36 -i- 0.021 to 0.311 ± 0.021 during the first day of treatment with pindolol and returned to 0.35 ± 0.022 during the fourth day of treatment. The transient decrease of of 0.37
±
0.012 to 0.31 ± 0.009 after
control
seven
days
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100 TABLE III Mean Values::!: SE of Systolic Time Intervals at Rest on a Control Day, Before DailyAdministration on Days 1, 2, 3, 4, and 7 artclAfter Discontinuation of Treatment with Atenolol 100 mg od, Propranolol 160 mg od, Pindolol 5 mg tid, and Nebivolol! 5 mg od in 7 Volunteers
QS, total electromechanical systole; PEP Preejection period; LVET = left ventricular ejection time. * p-values. Wilcoxon matched-pairs signed-ranks test versus control day (2-tailed probability; ns not significant) =
=
=
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101
FIG. 1. Mean values ± SE of the ratio PEP,/LVET, of the systolic time intervals on a control day, before daily administration on days 1, 2, 3, 4, and 7 during treatment (-); and after discontinuation of treatment (- - -) with atenolol 100 mg od, propranolol 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od in 7 volunteers. * p-values. Wilcoxon matched-pairs signed-ranks test versus control day (2-tailed probability); * p < 0.05.
the ratio PEP~/LVET~ was due to a decrease of the PEPC and an increase of the LVET,. No changes of the systolic time intervals occurred during treatment with atenolol and propranolol. The starting value of the ratio PEP./LVET, was 0.36 ± 0.021 and 0.34 -±- 0.014 respectively and the ratio after seven days of treatment was 0.34 ± 0.017 and 0.34 ± 0.018 respectively. During treatment with nebivolol the ratio PEPc/LVETc decreased significantly from a starting value of 0.37 ± 0.016 to 0.31 ± 0.008 after seven days of treatment (Figure 2). The results of the shortening of the postexercise LVETc during treatment with the different J3-adrenergic antagonists are depicted in Figure 3. The shortening of the postexercise LVETC, observed in control conditions, was significantly inhibited during treatment with atenolol, propranolol, and pindolol. Mean values of the shortening of the postexercise LVET, decreased from a control value of 48 msec ± 3.0 to 21 ± 3.9 after seven days of treatment with atenolol, from 47 msec ± 3.4 to 21 ± 4 with propranolol, and from 42 msec ± 3.7 to 6 ~- 3.3 with pindolol. During treatment with nebivolol no significant changes of the postexercise LVETC occurred. The mean values tended only to decrease from a control value of 45 msec ± 7.7 to 37 ± 3.9 after seven days of treatment with nebivolol. Discussion
Despite noteworthy
the very small number of volunteers involved in these series of experiments, it is that the control values of all hemodynamic parameters were comparable and not
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102
FIG. 2. Mean values ± SE of
preejection period (PEP,), left ventricular ejection time (LVET,), and the ratio PEP,/LVET, of the systolic time intervals on a control day; 3 hours after daily administration (-) of pindolol or 6 hours after daily administration (-) of nebivolol on days 1, 4, and 7; and on days I, 2, and 7 after discontinuation (- - -) of treatment with pindolol or nebivolol in 7 volunteers. * p-values. Wilcoxon matchedpairs, signed-ranks test versus control day (2-tailed probability); * p < 0.05.
different for each of the four sessions. Furthermore, seven days after discontinuation of the four study medications all variables returned to pretreatment values, so that it may be assumed that the frequent exercise tests had no influence on these parameters and gave no rise to training effects. The results of this study confirm our earlier observations that nebivolol inhibited the exercise-induced trachycardia and the rise in systolic blood pressure in normal healthy volunteers.2.3 In this experiment the effects on exercise heart rate were less pronounced, whereas the effects on exercise systolic blood pressure were comparable with the other J3-adrenergic antagonists tested. Indeed nebivolol 5 mg od lowered peak exercise heart rate and systolic blood pressure by 15% and 17% respectively, atenolol 100 mg od by 23% and 20%, propranolol 160 mg od by 21 % and 18%, and pindolol 5 mg tid by 22% and 15%. At rest, heart rate was significantly inhibited during treatment with atenolol and propranolol but not with pindolol. During treatment with nebivolol only a trend of decrease was observed. The decrease of
significantly
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103
FIG. 3. Mean values ± SE of the exercise-induced shortening of the LVET, on a control day (C); 3 hours after daily administration (zz2W) of pindolol or 6 hours after daily administration (®) of atenolol, propranolol, and nebivolol on * days l, 4, and 7; and on days 1, 2, and 7 after discontinuation (o ) of treatment in 7 volunteers. p-values. Wilcoxon matched-pairs, signed-ranks test versus control day (2-tailed probability).
systolic
and diastolic blood pressure at
rest was more
pronounced
with nebivolol than with
p-adrenergic antagonists tested. A progressive and sustained decrease of the PEP,/LVET, at rest was observed during treatment with nebivolol. The lowering of the ratio PEP,/LVET, is a valuable index of the improvement of overall left ventricular function.&dquo;9 This lowering was the result of a marked and significant shortening of the PEPc and a significant lengthening of the LVET,, indicating a combined effect on both preload and afterload. In normal volunteers the shortening of the PEP, in the absence of changes of Us20 might be interpreted as due to an increase of preload and improved left ventricular compliance.9&dquo;’ On the other hand the lengthening of the LVET, is suggestive of an increased stroke volume, due to a reduction of afterload. 10,12 In this respect, it is noteworthy that a significant increase of end-diastolic volume and stroke volume was observed in another study during treatment with nebivolol, with use of equilibrium radionuclide angiocardiography as an index of left ventricular function.4 These beneficial effects on cardiac function were not observed with the other (3-adrenergic antagonists tested whether or not secondary properties of (31 selectivity or intrinsic sympathomimetic activity were involved. Only a transient improvement of cardiac function was observed with pindolol, due probably to a temporary reduction of afterload mediated through @2-antagonism. During prolonged treatment with pindolol, however, the (3-blocking effects
the other
4
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104 rather than the intrinsic sympathomimetic activity appeared to predominate, so that all beneficial effects on cardiac performance were lost. Furthermore the shortening of the postexercise LVET,, which is the expression of the intrinsic positive inotropy of exercise,14.15 remained present during treatment with nebivolol, whereas a marked suppression of this shortening was observed during treatment with atenolol and propranolol. An almost complete abolition of the shortening of the postexercise LVET occurred progressively during treatment with pindolol. Prolongation of the latter parameter is generally observed in patients with ischemic disease 13,15 and during treatment with classical (3-adrenergic antagonists’ and is considered to be indicative of diminished myocardial contraction. 16-1g Therefore, the shortening of the postexercise LVET, observed during treatment with nebivolol suggests that cardiac function remains optimally preserved during exercise. Lastly nebivolol appears tu be a potent J31-adrenergic antagonist with a long duration of action. Forty-eight hours after discontinuation of treatment with nebivolol 5 mg od, exercise tachycardia and the exercise-induced increase of systolic blood pressure and systolic time intervals were still significantly different from control values. Twenty-four hours after discontinuation all these values were even comparable with maximal effects during the treatment period with nebivolol. The pharmacologic mechanism underlying the unusual hemodynamic profile of nebivolol is still poorly understood. In dogs nebivolol, unlike classical ~3-adrenergic antagonists, increases stroke volume and lowers systemic vascular resistance.’ The nature of this phenomenon is unknown. Intrinsic sympathomimetic activity of nebivolol could be ruled out and there is a lack of major effects on other receptor-mediated responses at doses that I block (3-receptors.’ Nevertheless, from all the available data, evidence is growing that nebivolol presumably shares an unusual combination of pharmacologic activities. In this respect it is noteworthy that nebivolol is a mixture of two enantiomers. In a preliminary study (personal communication), we could observe that one of these enantiomers behaved as a classical J3-adrenergic antagonist, reducing exercise heart rate and systolic blood pressure but not beneficially influencing the hemodynamic profile, whereas the other enantiomer shared only the ancillary cardiac stimulatory activities, without having (3-blocking properties.
Conclusions
Although the precise mechanism of action is not yet elucidated, neh:r olol appears to be a potent and long-acting, selective J31-adrenergic antagonist, with ~11 intriguing hemodynamic profile, improving left ventricular function at rest and offscLting the negative influence of classical (3-blockade on myocardial contractility during exercise. ,~ Acknowledgment We
are
indebted to An Baisier for statistical evaluation and for her
help
in
preparing
the
figures. J. De Cree, M.D. FL CA. Clinical Research Unit St. Bartholomeus Jan Palfijn Hospital Long Bremstraat 70 B-2060 Merksem, Belgium
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105
References 1. Van de Water A, Janssens W, Van Nueten J, et al: The pharmacological and haemodynamic profile of nebivolol, a chemically novel, potent and selective β1-adrenergic antagonist. J Cardiovasc Pharmacol 11:
552-563, 1988. Crée J, Geukens H,
Leempoels J, et al: Haemodynamic effects in man during exercise of a single oral dose of nebivolol (R 67555), a new beta-1andrenoceptor blocking agent: A comparative study with atenolol, pindolol and propranolol. Drug Dev Res
2. De
8:109-117, 1986. 3. De Crée J, Geukens H, Cobo C,
al: Subacute and
et
hemodynamic effects of nebivolol in man at rest during exercise. Angiology 38:440-448, 1987. 4. De Crée J,
5.
10.
11.
12.
13.
Francken PH, Vandevivere J, et al:
Hemodynamic effects of nebivolol in men: Comparison of radionuclide angiocardiography with systolic time intervals. Angiology 39:526-534, 1988. Bruce RA: Multistage treadmill test of submaximal and maximal exercise. In: Exercise Testing and Training of Apparently Healthy Individuals: A Handbook for Physicians, ed. by Naughton J, Hellerstein HK. New York: American Heart Association, 1972.
6. De Crée J, Geukens H, Verhaegen H: A survey of 15 years experience with systolic time intervals. Acta Antwerpiensia 4:2-18, 1987. 7. Weissler AM, Garrard CL: Systolic time intervals in cardiac disease. Mod Concepts Cardiovasc Dis 40:1-4, 1971. 8. Siegel S: Nonparametric Statistics. New York: McGraw-Hill, 1956, pp 75-83. 9. Lewis RP, Rittgers S. Forester WF, et al: A critical review of the systolic time intervals. In: Reviews of
ed. by Weissler AM. Circulation 56:146-158, 1977. Lewis RP, Boudoulas H, Leier CV, et al: Usefulness of the systolic time intervals in cardiovascular clinical cardiology. Am Clin Climatol Assoc 93:108-120, 1981. Stem HC, Matthews JH, Belz GG: Influence of dihydralazine induced afterload reduction on systolic time intervals and echocardiography in healthy subjects. Br Heart J 52:435-439, 1984. Nakamura Y, Wiegner AW, Gaasch WH, et al: Systolic time intervals: Assessment by isolated cardiac muscle studies. JACC 2:973-978, 1983. Pouget JM, Harris WS, Mayron BR, et al: Abnormal responses of the systolic time intervals to exercise in patients with angina pectoris. Circulation 43:289-298, 1971. Lewis RP, Marsch DG, Sherman JA, et al: Enhanced diagnostic power of exercise testing for myocardial ischemia by addition of post-exercise left ventricular ejection time. Am J Cardiol 39:767-775, 1977. Bowlby JR: The effect of exercise on left ventricular ejection time in patients with hypertension or angina pectoris. Am Heart J 97:348-350, 1979. Maher JT, Beller GA, Ransil BJ, et al: Systolic time intervals during submaximal and maximal exercise in man. Am Heart J 87:334-342, 1974. Bouchard RE, Parnes WD, Mandell BE, et al: Systolic time intervals before and after maximal exercise treadmill testing for evaluation of chest pain. Chest 71:479485, 1977. Cokkinos DV, De Puey EG, Rivas AH, et al: Correlations of systolic time intervals and radionuclide angiography at rest and during exercise. Am Heart J 109:104112, 1985.
Contemporary Laboratory Methods,
14.
15.
16.
17.
18.
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of the Subacute
Hemodynamic
Propranolol, Pindolol,
Effects
and Nebivolol
M.D., F.I.C.A. Carlos Cobo, M.D.
Jean De Crée,
Geukens and
Hedwig Herman
Verhaegen, M.D., Ph.D.,
F.I.C.A.
MERKSEM, BELGIUM
Abstract In an observer-blind four-way crossover study, 7 healthy volunteers received in random sequence, one month apart, atenolol 100 mg od, propranolol (slow release) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od for a period of seven days, followed by a single-blind placebo washout period of seven days. The decrease of peak exercise heart rate and systolic blood pressure was significant 0.02) and comparable for the four drugs studied and varied between 15% (p and 23% for heart rate and between 15% and 20% for systolic blood pressure. Although no statistically significant difference was observed among the four drug regimens, the decrease of peak exercise heart rate was less pronounced with nebivolol than with the three reference beta-blocking agents. The ratio of the preejection period (PEP ), an c ) to the left ventricular ejection time (LVET c indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. c /LVET PEP with nebivolol from a control value of and significantly improved progressively 0.37 ± 0.012 to 0.31 ± 0.009 (p = 0.03) after seven days of treatment, owing to a decrease in PEP c and an increase in LVET , suggestive of a combined effect c both on preload and afterload. Postexercise LVET , an index of the intrinsic c positive inotropy of exercise, was significantly suppressed by atenolol, propranolol, and pindolol, but not during treating with nebivolol. These data suggest that nebivolol is a β1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular com=
pliance.
From the Clinical Research Unit St. Bartholomeus, Jan
Palfijn Hospital, Merksem, Belgium
95
Downloaded from ang.sagepub.com at OAKLAND UNIV on July 8, 2015
96 Introduction
;.
.
:
:
.
. ; :r
Nebivolol is a chemically novel J3-adrenergic antagonist.’ In vitro nebivolol has been found to be a potent antagonist of J31-adrenergic receptors with greater selectivity for the J31-adrenergic receptor than any of the reference compounds has.’ Nebivolol has an unusual combination of pharmacologic properties. In closed-chest anesthetized dogs, besides the @-blocking properties, nebivolol at low dose slightly decreased systemic vascular resistance and increased stroke volume and cardiac output. In contrast to classical J3-adrenergic antagonists, nebivolol acutely I lowers systolic and diastolic blood pressure in spontaneously hypertensive rats.’ In man, nebivolol significantly attenuates exercise heart rate and systolic blood pressure after acute and subacute oral treatment; improves left ventricular performance at rest, as measured with systolic time intervals and with equilibrium radionucline angiocardiography, and keeps the intrinsic positive inotropy of exercise unaffected during prolonged treatment . 2-4 In hypertensive patients nebivolol significantly decreases systolic and diastolic blood pressure for a substantial 1 period of time after a single oral dose.’ The present study was conducted to assess the subacute hemodynamic profile of nebivolol in human volunteers in comparison with those of three classical J3-adrenergic antagonists.
..
~
Materials and Methods
:
>
. :
.,
.. -
Seven
apparently healthy volunteers, aged between twenty-five and forty-eight (median: thirty-six) years, participated in this study. Each subject gave his informed consent to the experimental procedure. The volunteers were requested not to change their personal habits of physical activity, alcohol ingestion, or tobacco consumption throughout the study. They were °
~ allowed to take any other medication. ’~= &dquo;-1’: °i&dquo;~-~~~.. Before and after exercise, observer-blind blood pressure measurements were assessed with an automated device, consisting of an inflatable cuff and an oscillatory detection system for systolic and diastolic blood pressure with all values registered on a built-in recorder. Blood pressure measurements were always done in supine position after a rest of ten minutes in a quiet room. During exercise systolic blood pressure measurements were done with a sphygmomanometer and a stethoscope always by the same observer at the left upper extremity. A standardized multistage exercise test of nine minutes’ duration was performed on a 5 treadmill, with adjustable speed and inclination, and by use of a modified protocol of Bruce.5 For the first three minutes the volunteers had to walk at a speed of 2.5 mph, at an inclination of 10%. For the next three minutes, speed was increased to 3.4 mph at an inclination of 12% and for the last three minutes to 4.2 mph at an inclination of 14%. Continuous ECG monitoring on an oscilloscope and recording of the peripheral leads and a precordial lead (V5) on a six-channel instrument allowed measurements of heart rate every minute during exercise and a recovery period up to six minutes after the end of exercise. Systolic blood pressure measurements were done every three minutes during exercise and at one, three, and six minutes during recovery. Systolic time intervals were measured from simultaneous recordings (at a paper speed of 100 mm/sec) of a peripheral lead of the ECG, phonocardiogram (pulse phonotransducer), and carotid pulse wave. Five to ten consecutive cardiac cycles were analyzed and averaged for the
not
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.
97
following parameters: Q$2, total electromechanical systole; LVET, left ventricular ejection time; PEP, preejection period. LVET, PEP and QS, were corrected for heart rate according to our resting supine regression equations~: LVETC = -1.2396 (72-HR) + LVET, PEP, = -0.4187 (72-HR) + PEP and QS2C = -1.7112 (72-HR) + QS2, which are similar to that of Weissler al.’ The ratio of the PEP,
to the LVETC (PEP./LVET,) was used as an index of left ventricular of An performance. analysis variance showed the residual variation to be negligible ( ± 3.5%) so that differences as small as 5% are representative for real changes of left ventricular
et
6
performance . The difference between a measure of the LVET, before exercise and thirty seconds after the end of exercise was also calculated and expressed as LVET,. For this purpose the postexercise regression equation LVETC = -0.7708 (72-HR) + LVET was used to correct for 6 heart rate. Statistical evaluation was calculated by means of the Wilcoxon matched-pairs, signed-ranks 8 test, two-tailed probability.~ Each subject received in random sequence and in a four-way crossover fashion one month apart for each session the following four beta-adrenergic antagonists for seven days, followed by a seven-day single-blind placebo period: atenolol 100 mg od, propranolol (slow-release formulation) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od. Study medication was always taken at breakfast and for pindolol additionally at noon and at 6 P M. All measurements were performed at exactly the same time of the day. Measurements of systolic time intervals at rest, systolic and diastolic blood pressure, and heart rate were done on a control day and before daily intake of the study medication, on days 1, 2, 3, 4, and 7 during p-blocker treatment and on days l, 2, and 7 during subsequent placebo treatment. An exercise test and the above-mentioned measurements at rest were also performed six hours after administration of atenolol, propranolol, and nebivolol and three hours after administration of pindolol on a control day, on days 1, 4, and 7 during (3-blocker treatment and on days l, 2, and 7 during subsequent placebo treatment. Since it was impossible to administer all drugs in identical form, we instructed an independent observer (a pharmacist of our department) to distribute the study medication to the volunteers. In order to keep the experiment observer-blind, the volunteers were requested to exchange no information about their medication to the observers. .
Results No significant differences were observed during the baseline examinations during the four different sessions. The results for heart rate and systemic blood pressure at rest, for exercise heart rate and systolic blood pressure, and for systolic time intervals at rest and after exercise were comparable and not significantly different at baseline evaluation for the four different sessions in these 7 volunteers (Tables I, II, and III, Figures 1 and 3). The results of the exercise-induced changes of heart rate and systolic blood pressure during the administration of the different J3-adrenergic antagonists are summarized in Table I. The increases of heart rate and systolic blood pressure during exercise and during recovery were significantly inhibited (p = 0.02) from the first day of treatment and during the seven days of treatment with the four study medications. At peak exercise mean heart rate decreased from a control value of 156 beats/min ± 1.4 to 120 ± 4.0 on the seventh day of treatment with
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98 5.6 to 125 :i: 4.0 during treatment with propranolol, from 162 beats/min z- 4.6 to 127 ± 3.2 with pindolol, and from 154 beats/min ± 6.6 to 131 ± 4.9 with nebivolol. Mean maximal systolic blood pressure was reduced from a control value of 164 mmHg ± 4.7 to 121 ± 5.5 on the seventh day of treatment with atenolol, from 163 mmHg ± 11.9 to 134 ± 7.8 during treatment with propranolol, from 159 mmHg ± 4.1 to 136 ± 5.3 with pindolol, and from 164 mmHg ± 7.2 to 136 ± 8.8 with nebivolol. After discontinuation of treatment, exercise heart rate remained significantly reduced for up to two days after the last dose of atenolol, propranolol, and nebivolol, but with pindolol the effects on exercise heart rate were not significantly different from control values from twenty-four hours after the last dose. Exercise systolic blood pressure remained significantly different for up to two days after discontinuation of treatment with atenolol and nebivolol, whereas with propranolol and pindolol no such differences were observed from twenty-four hours after the last dose (Table I).
atenolol, from 159 beats/min
.
~-
TABLE I Metiti Values ::t SE of
Test
on all
Ma.rinral Heart Rate
C olltrol Day.
on
(Beats/Min) (HR) and Systolic Blood Pressure (mmHg) (SBP) During an Exercise
Days l, 4, and 7 During Treatment and on Days 1, 2, and 7After Discontinuation ofTreatment Propranolol 160 mg od, Pindolol 5 ing tid, and Nebivolol 5 mg od in 7 Volunteers
with Atenolol 100 ing od,
p-values.
Wilcoxon
matched-paira signed-rank,,
test versus
control
day (2-tailed probability:
ns
=
not
significant)
values of heart rate and of systolic and diastolic blood pressure are given in Table II. At rest, heart rate decreased significantly during treatment with atenolol and propranolol but not during treatment with pindolol and nebivolol. Systolic blood pressure at rest decreased significantly from a starting value of 117 mmHg ± 2.6 to 110 ± 4.4 after seven days of treatment with atenolol, from 116 mmHg ± 2.8 to 1111 ± 4.0 with propranolol, and from 119 mmHg ± 2.4 to 101 ± 3.8 with nebivolol. Diastolic blood pressure at rest decreased significantly with nebivolol from a starting value of 72 mmHg ± 1.5 to 61 ± 2.5 after seven days of treatment. During treatment with pindolol systolic and diastolic blood pressure did not change significantly. The significant reduction of resting values of systolic and diastolic blood pressure during treatment with nebivolol lasted for two days after discontinuation of treatment
Resting
(Table II). The results of the different parameters of the systolic time intervals measured in the morning before daily administration of the study medication are shown in Table III and Figure 1. The ratio of the PEP./LVET, did not change significantly during treatment with atenolol, propranolol, and pindolol, except for a slight but significant lengthening of the LVET, on the seventh day during treatment with atenolol and propranolol and except for a significant increase of the QS2,’ during treatment with propranolol. In contrast, the ratio of the PEPc/LVETc progressively and significantly decreased during treatment with nebivolol from a starting value
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99 TABLE II Mean Values ± SE of Heart Rate and of Systolic and Diastolic Blood Pressure at Rest on a Control Duy, Befi>re Daily Administration on Days 1, 2, 3, 4, and 7 During Treatment and on Days /, 2, and 7 After Discontinuation of Treatment with Atenolol 100 mg od, Propranolol 160 mg od, Pindolol 5 mg tid, and Nebivolol 5 mg od in 7 Volunteers
*
p-values.
Wilcoxon
matched-pairs signed-ranks
test versus
day (2-tailed probability;
ns
=
not
significant)
of treatment. The decrease of the ratio PEP./LVET, was due to a significant shortening of the PEP, and a significant lengthening of the LVET,. Mean values of PEP, decreased from an initial value of 105 msec ± 4.3 to 96 ± 2.3 after seven days of treatment and mean values of LVET, increased from a control value of 286 msec ± 3.7 to 305 ± 2.4. These significant changes in Pep LVET,, and PEP./LVET, persisted for up to two days after discontinuation of treatment with nebivolol. The results of the systolic time intervals, measured in the afternoon six hours after daily intake of atenolol, propranolol, and nebivolol and three hours after intake of pindolol, are similar to those measured in the morning before daily administration of the study medication, except for a transient and significant decrease of the ratio PEP)LVETc observed only during the first day of treatment with pindolol (Figure 2). Mean values of the ratio PEP,/LVET, decreased from a control value of 0.36 -i- 0.021 to 0.311 ± 0.021 during the first day of treatment with pindolol and returned to 0.35 ± 0.022 during the fourth day of treatment. The transient decrease of of 0.37
±
0.012 to 0.31 ± 0.009 after
control
seven
days
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100 TABLE III Mean Values::!: SE of Systolic Time Intervals at Rest on a Control Day, Before DailyAdministration on Days 1, 2, 3, 4, and 7 artclAfter Discontinuation of Treatment with Atenolol 100 mg od, Propranolol 160 mg od, Pindolol 5 mg tid, and Nebivolol! 5 mg od in 7 Volunteers
QS, total electromechanical systole; PEP Preejection period; LVET = left ventricular ejection time. * p-values. Wilcoxon matched-pairs signed-ranks test versus control day (2-tailed probability; ns not significant) =
=
=
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101
FIG. 1. Mean values ± SE of the ratio PEP,/LVET, of the systolic time intervals on a control day, before daily administration on days 1, 2, 3, 4, and 7 during treatment (-); and after discontinuation of treatment (- - -) with atenolol 100 mg od, propranolol 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od in 7 volunteers. * p-values. Wilcoxon matched-pairs signed-ranks test versus control day (2-tailed probability); * p < 0.05.
the ratio PEP~/LVET~ was due to a decrease of the PEPC and an increase of the LVET,. No changes of the systolic time intervals occurred during treatment with atenolol and propranolol. The starting value of the ratio PEP./LVET, was 0.36 ± 0.021 and 0.34 -±- 0.014 respectively and the ratio after seven days of treatment was 0.34 ± 0.017 and 0.34 ± 0.018 respectively. During treatment with nebivolol the ratio PEPc/LVETc decreased significantly from a starting value of 0.37 ± 0.016 to 0.31 ± 0.008 after seven days of treatment (Figure 2). The results of the shortening of the postexercise LVETc during treatment with the different J3-adrenergic antagonists are depicted in Figure 3. The shortening of the postexercise LVETC, observed in control conditions, was significantly inhibited during treatment with atenolol, propranolol, and pindolol. Mean values of the shortening of the postexercise LVET, decreased from a control value of 48 msec ± 3.0 to 21 ± 3.9 after seven days of treatment with atenolol, from 47 msec ± 3.4 to 21 ± 4 with propranolol, and from 42 msec ± 3.7 to 6 ~- 3.3 with pindolol. During treatment with nebivolol no significant changes of the postexercise LVETC occurred. The mean values tended only to decrease from a control value of 45 msec ± 7.7 to 37 ± 3.9 after seven days of treatment with nebivolol. Discussion
Despite noteworthy
the very small number of volunteers involved in these series of experiments, it is that the control values of all hemodynamic parameters were comparable and not
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102
FIG. 2. Mean values ± SE of
preejection period (PEP,), left ventricular ejection time (LVET,), and the ratio PEP,/LVET, of the systolic time intervals on a control day; 3 hours after daily administration (-) of pindolol or 6 hours after daily administration (-) of nebivolol on days 1, 4, and 7; and on days I, 2, and 7 after discontinuation (- - -) of treatment with pindolol or nebivolol in 7 volunteers. * p-values. Wilcoxon matchedpairs, signed-ranks test versus control day (2-tailed probability); * p < 0.05.
different for each of the four sessions. Furthermore, seven days after discontinuation of the four study medications all variables returned to pretreatment values, so that it may be assumed that the frequent exercise tests had no influence on these parameters and gave no rise to training effects. The results of this study confirm our earlier observations that nebivolol inhibited the exercise-induced trachycardia and the rise in systolic blood pressure in normal healthy volunteers.2.3 In this experiment the effects on exercise heart rate were less pronounced, whereas the effects on exercise systolic blood pressure were comparable with the other J3-adrenergic antagonists tested. Indeed nebivolol 5 mg od lowered peak exercise heart rate and systolic blood pressure by 15% and 17% respectively, atenolol 100 mg od by 23% and 20%, propranolol 160 mg od by 21 % and 18%, and pindolol 5 mg tid by 22% and 15%. At rest, heart rate was significantly inhibited during treatment with atenolol and propranolol but not with pindolol. During treatment with nebivolol only a trend of decrease was observed. The decrease of
significantly
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103
FIG. 3. Mean values ± SE of the exercise-induced shortening of the LVET, on a control day (C); 3 hours after daily administration (zz2W) of pindolol or 6 hours after daily administration (®) of atenolol, propranolol, and nebivolol on * days l, 4, and 7; and on days 1, 2, and 7 after discontinuation (o ) of treatment in 7 volunteers. p-values. Wilcoxon matched-pairs, signed-ranks test versus control day (2-tailed probability).
systolic
and diastolic blood pressure at
rest was more
pronounced
with nebivolol than with
p-adrenergic antagonists tested. A progressive and sustained decrease of the PEP,/LVET, at rest was observed during treatment with nebivolol. The lowering of the ratio PEP,/LVET, is a valuable index of the improvement of overall left ventricular function.&dquo;9 This lowering was the result of a marked and significant shortening of the PEPc and a significant lengthening of the LVET,, indicating a combined effect on both preload and afterload. In normal volunteers the shortening of the PEP, in the absence of changes of Us20 might be interpreted as due to an increase of preload and improved left ventricular compliance.9&dquo;’ On the other hand the lengthening of the LVET, is suggestive of an increased stroke volume, due to a reduction of afterload. 10,12 In this respect, it is noteworthy that a significant increase of end-diastolic volume and stroke volume was observed in another study during treatment with nebivolol, with use of equilibrium radionuclide angiocardiography as an index of left ventricular function.4 These beneficial effects on cardiac function were not observed with the other (3-adrenergic antagonists tested whether or not secondary properties of (31 selectivity or intrinsic sympathomimetic activity were involved. Only a transient improvement of cardiac function was observed with pindolol, due probably to a temporary reduction of afterload mediated through @2-antagonism. During prolonged treatment with pindolol, however, the (3-blocking effects
the other
4
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104 rather than the intrinsic sympathomimetic activity appeared to predominate, so that all beneficial effects on cardiac performance were lost. Furthermore the shortening of the postexercise LVET,, which is the expression of the intrinsic positive inotropy of exercise,14.15 remained present during treatment with nebivolol, whereas a marked suppression of this shortening was observed during treatment with atenolol and propranolol. An almost complete abolition of the shortening of the postexercise LVET occurred progressively during treatment with pindolol. Prolongation of the latter parameter is generally observed in patients with ischemic disease 13,15 and during treatment with classical (3-adrenergic antagonists’ and is considered to be indicative of diminished myocardial contraction. 16-1g Therefore, the shortening of the postexercise LVET, observed during treatment with nebivolol suggests that cardiac function remains optimally preserved during exercise. Lastly nebivolol appears tu be a potent J31-adrenergic antagonist with a long duration of action. Forty-eight hours after discontinuation of treatment with nebivolol 5 mg od, exercise tachycardia and the exercise-induced increase of systolic blood pressure and systolic time intervals were still significantly different from control values. Twenty-four hours after discontinuation all these values were even comparable with maximal effects during the treatment period with nebivolol. The pharmacologic mechanism underlying the unusual hemodynamic profile of nebivolol is still poorly understood. In dogs nebivolol, unlike classical ~3-adrenergic antagonists, increases stroke volume and lowers systemic vascular resistance.’ The nature of this phenomenon is unknown. Intrinsic sympathomimetic activity of nebivolol could be ruled out and there is a lack of major effects on other receptor-mediated responses at doses that I block (3-receptors.’ Nevertheless, from all the available data, evidence is growing that nebivolol presumably shares an unusual combination of pharmacologic activities. In this respect it is noteworthy that nebivolol is a mixture of two enantiomers. In a preliminary study (personal communication), we could observe that one of these enantiomers behaved as a classical J3-adrenergic antagonist, reducing exercise heart rate and systolic blood pressure but not beneficially influencing the hemodynamic profile, whereas the other enantiomer shared only the ancillary cardiac stimulatory activities, without having (3-blocking properties.
Conclusions
Although the precise mechanism of action is not yet elucidated, neh:r olol appears to be a potent and long-acting, selective J31-adrenergic antagonist, with ~11 intriguing hemodynamic profile, improving left ventricular function at rest and offscLting the negative influence of classical (3-blockade on myocardial contractility during exercise. ,~ Acknowledgment We
are
indebted to An Baisier for statistical evaluation and for her
help
in
preparing
the
figures. J. De Cree, M.D. FL CA. Clinical Research Unit St. Bartholomeus Jan Palfijn Hospital Long Bremstraat 70 B-2060 Merksem, Belgium
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105
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