Comparison of the Subacute Hemodynamic Effects

of Atenolol, Propranolol, Pindolol, and Nebivolol

Jean De Cree. M.D., F.I.C.A.

Carlos Cobo, M.D.
Hedwig Geukens '
and
Herman Verhaegen, M.D., Ph.D.. F.I.C.A.

MERKSBM, BKLGIUM

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 signiflcant
(p = 0.02) and comparable for the four drugs studied and varied between 15%
and 23% for heart rate and between 15% and 20% for systolic blood pressure.
Although no statistically signiflcant difference was observed among the four
drug regimens, the decrease of peak exercise heart rate was le.ss pronounced
with nebivolol than with the three reference beta-blocking agents. The ratio of
the preejection period (PEP,) to the left ventricular ejection time (LVET,), an
indirect measure of left ventricular performance, tended to increase with
atenolol and propranolol and remained unchanged with pindolol. PEPyLVET,
progressively and signiflcantly improved with nebivolol from a control value of
0.37 ± 0.012 to 0.31 ± 0.009 (p = 0.03) after seven days of treatment, owing
to a decrease in PEP, and an increase in LVET,, suggestive of a combined effect
both on preload and afterload. Postexercise LVET,, an index of the intrinsic
positive inotropy of exercise, was signiflcantly suppressed by atenolol, pro-
pranolol, and pindolol, but not during treating with nebivolol.
These data suggest that nebivolol is a pi-selective adrenergic antagonist with
an unusual hemodynamic proflle, probably improving left ventricular com-
pliance.

From the Clinical Research Unit St. Bartholomeus. Jan Palfijn Hospital, Merksem, Belgium
95
96 Angiology—77i^ Journal of Vascular Diseases February 1990
introduction
Nebivolo! is a chemically novel p-adrenergic antagonist.' In vitro nebivolol has been found
to be il potent antagonist of p I-adrenergic receptors with greater selectivity for the pi-adrener-
gic receptor than any of the reference compounds has.' Nebivolol has an unusual combination
of pharmacoiogic properties. In closed-chest anesthetized dogs, besides the p-blocking proper-
ties, nebivolol at low dose slightly decreased systemic vascular resistance and increased stroke
volume and cardiac output. In contrast to classical p-adrenergic antagonists, nebivolol acutely
lowers systolic and diastolic blood pressure in spontaneously hypertensive rats.' In man.
nebivotol 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." * In hypertensive
patients nebivolol significantly decreases systolic and diastolic blood pressure for a substantial
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 ^-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
not allowed to take any other medication.
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 sphyg-
momanometer 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
treadmill, with adjustable speed and inclination, and by use of a modified protocol of Bruce.'
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 {V,) 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
 De Cr^e—Hemodynamic Effects of Nebivolol 97
following parameters: QS., 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": LVET, = -1.2396 (72-HR) + LVET. PEP, = -0.4187
(72-HR) + PEP and QS,,- = -1.7112 (72-HR) + QS,, which are similar to that of Weissler
et al.'The ratio of the PEP, to the LVET, (PEP./LVEX) was used as an index of left ventricular
performance. An analysis of 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
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 ALVET,. For this purpose the
postexercise regression equation LVET, = -0.7708 (72-HR) -F LVET was used to correct for
heart rate.*"
Statistical evaluation was calculated by means of the Wilcoxon matched-pairs, signed-ranks
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 lor 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 nebivoiol 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 I, 2. 3, 4, and 7 during p-blocker
treatment and on days I, 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 p-blocker treatment and on days 1, 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 1, 11, 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 p-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
98 Angioiogy—77if Journal of Vascular Diseases February 1990
atenolol. from 159 beats/min ± 5.6 to 125 ± 4.0 during treatment with propranolol. from
162 beats/min ± 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).

TABLE 1
Mcini Vtihu:\ ± SE i\j Maximal Hcitn Raw (Bi'otslMini (tiR) and Systolic Blood Pressure fmniHg) (SBP) Diiriiifi an F.xercise
Test <iii tin Ctmtnil Day. on Days I. 4. and 7 During Trcatinrnt and on Daws /. 2. and 7 After Di.scoinirtucition ofTreatmvnt
wilh Atenolol 100 mg od. Propra)u>iol 160 mg od. Pindolol 5 mg lid. and Nchivolol 5 mg od in 7 Volunteers
criol.ll fropran>.lol PmJolnl No

HR SBP tlR SBP HR SHP HR SBP

a- Irol iia\ 156 ± 1 4 — I64±4.7 „ 159 r 5.6 — !63± 11.9 — 162 ± 4 . 6 — 54±4 1 — 154 ±6,6 — I64±7.2 —
>.i 1 120* 2 1 1.02 126 ±6.6 1.02 I24±2.7 0.02 142 ±8.6 0.03 130 ±4.3 0.02 41 ±7 3 ).I13 135 ±6.4 11.02 133 ±6.3 0.02
DJ 4 IIN± 3.1 t.O2 122 ±5,3 0.02 I2O±4.5 0.02 I36±6.l 0,03 13O±2X 0.02 46 ±5 3 ).O2 129 ±4.3 0,02 I36±f!.7 0.02
Da 7 120* 4.0 1 0 ] I 2 I ± 5 , 5 1,02 125 ± 4 . 0 0.02 I34±7N 0.O2 I27±3 2 0,02 36 ±5 3 0,02 131 ±4.9 0.02 l.t6±S.K 0.02
Xl 1 posi )34± 4.2 ).O3 I3K±4 6 103 14(1 ± 5 4 no: 14716 1 ns 149 T 1 i ns 55 ±7 5 ns 1,15 ±6.0 0.02 I43±ll 2 0.01
Da 2piisi 152* 24 1.03 146:^3 0 102 146 + 5.1 0.05 I49±7.O ns I5K±4.4 ns 63 ±7 y ns I46±4.7 0.05 I54±').K 0.03
Du 7 posi 156- 4 0 IS 147 ±6 1 ns 155 ± 4 5 ns I.M ^ 7 1} ns Ifil - ' 2 ns f i : t .s -'' ns 152 ±6.1 ns I56± II 3 ns

' p-valui"N. Will. iKiin iiialfhfd-pairs s gnod-ranks i 'si MTsus L'oniro dav 2-Lailed pr ibahiliiy. ns - )(>l SlgiitiL-ai ,)

Resting values of heart rate and of systolic and diastotic blood pressure are given in Table
II. At rest, heart rate decreased significantly during treatment with atenolo! 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 III ± 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
(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
I. 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 QS:, during treatment with propranolol. In contrast, the ratio of the PEP,/LVEX
progressively and significantly decreased during treatment with nebivolol from a starting value
 De C/"^^—Hemodynamic Effects of Nebivolol 99
TABLt II
Mt'u/J Vuhtcs ± SE of Hean Riiiv and of Systolic and Diasiolic Blood Fressitrc ui Re.si on a Contmi Day. Bcjtiif Duilv
Administration on Days /. 2, 3, 4. and 7 During Treatment and on Days /. 2. und 7 After Discontinuation of Treatment
with Awnolol 100 mg od, Propranolol 160 mg od, Pindolo! 5 mg tid. and Nehivolol 5 mg od in 7 Volunlccrs

Atenolol Propranolol Pindolc. Nebivolol

Heart rate (beats/min)
Control day 72 ±5.2 — 72±4.7 — 70 ±3.8 — 72 ± 6.1 —
Day 1 68 ±4,5 ns 70 ±3.2 ns 70 ±4.2 ns 72 ±3.8 ns
Day 2 64 ±4.3 0.03* 58 ± 1.6 ns 75 ±3.7 ns 69 ±4.5 ns
Day 3 60±4.2 0.02 57 ± 1.9 0.02 76±2.4 ns 64 ±3,5 ns
Day 4 63±4.6 0.03 58 ±2.7 0.02 72 ±3.4 ns 66 ±3,8 ns
Day 7 65±4.7 0.02 60 ±3.4 ns 71 ±2.2 ns 66±4.8 ns
Day 1 post 64 ±5,1 0.03 60 ± 2.9 0.03 80 ±3.7 ns 65 ±3.5 ns
Day 2 post 71±4.4 ns 62 + 3.0 0.03 82 ±3.6 ns 68±4.6 ns
Day 7 post 74 ±5.1 ns 73 ±5.4 ns 78±3.2 ns 74 ±3.6 ns

Systolic blood pressure (mmHg)

Contro! day I17±2.6 — I]6±2,8 — 1I7±2.4 — 1I9±2.4 —
Day I II7±2,6 ns 112 ±3.1 ns 116 ±3.0 ns 116±2,3 ns
Day 2 I12±2.5 ns 108 ±4.5 ns 115 ±3.5 ns 106 ±4.0 0.02
Day 3 111 ± 3 . 5 ns 107 ±3.8 0.03 1I6±3.2 ns 107 ±3.8 0.02
Day 4 108 ± 3 , 3 0.03 109 ±3,9 0.03 1I7±2,9 ns 105 ±3.5 0.02
Day 7 ll()±4.4 ns 111 ±4.0 ns 1I7±2.4 ns 101 ±3.8 0.02
Day 1 post IO7±I.5 0.03 109 ±3.8 ns 1I4±2.O ns 1O4±3.O 0.02
Day 2 post 116±3.4 ns 114 ±4.5 ns 115 ±2.9 ns 110 ±3.1 0.02
Day 7 post 116±2.8 ns 116 ±4,1 ns II8±2.6 ns II4±2.8 ns

Diastolic blood pressure (mmHg)

Control day 74 ±1.9 — 76 ±2.3 — 76± 1.7 — 72 ± L5 —
Day 1 73±I,K ns 74 ±2,4 ns 77± 1.8 ns 72±3.l ns
Day 2 69 ±0.9 ns 69 ±2,5 0,02 74 ±1.3 ns 63 ±2.4 0.02
Day 3 69 ±1,3 ns 71 ±2.3 ns 74 ±2.1 ns 64 ±3.7 ns
Day 4 70±l.l ns 7O±I.5 0.03 74 ±1.7 ns 63 ±3.4 ns
Day 7 70 ± 1.8 ns 73 ±3.1 ns 77 ±1.8 ns 61 ±2.5 0.02
Day 1 pos! 68±0.X ns 7O±2.2 0.02 76 ±2.0 ns 62± 1.8 0.03
Day 2 post 73 ±2.1 ns 74 ±2,1 ns 74 ±2.0 ns 64± 1.7 0.03
Day 7 post 73±2.l IIS 74 ±2.1 ns 77±2.l ns 69 ±2.6 ns
* p-values- Wilcoxon mali:hed-pairs signed-ranks test versus control day (2-tailed probability; ns ••=- not signilicantj

of 0.37 ± 0.012 to 0.31 ± 0.009 after seven days 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,, LVEX, and PEP./LVEX
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 PEPyLVET, observed only during the first day
of treatment with pindolol (Figure 2). Mean values ofthe ratio PEPyLVET, decreased from a
control value of 0.36 ± 0.021 to 0.31 ± 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
100 Angioiogy—The Journal of Vascular Diseases February 1990
TABLE III
Mean Vahie.\ ± SE ojSystolicTime Intervals at Rest on a Conlrol Day. Before Daily Administration on Days 1.2.3,4. and 7
and After Discontinuation of Treatment with Atenolol 100 mg od, Propranolol 160 mg od. Pindolol 5 mg tid,
and Nehivolol 5 mg od in 7 Volunteers

Atenolol Propranolo! Pindoloi Nebivolol

QS:
Control dyy 402 ± 5 ,9 391 ± 3 .6 — 395 ±7,6 — 391 ±7 ,4 —
Day 1 401 ± 4 ,6 ns 403 ± 5 ,0 0,03* 394 ±4,8 ns 390 ± 6 ,9 ns
Day 2 404 ± 4 .9 ns 403 :t 4 ,5 0,03 388 ±4,7 ns 394 ± 6 .0 ns
Day 3 404±4 .7 ns 403 ± 7 .3 0,03 389 ±7,1 ns 393 ± 5 .6 ns
Day 4 411 ±6. I ns 397 ± 5 ,4 0,05 392 ±8,0 ns 394 ± 6 ,0 ns
Day 7 407 ± 6 ,3 ns 404 ± 4 ,3 0,02 391 ±5,7 ns 399 ±3.7 ns
Day 1 poM 404 ± 6 ,4 ns 403 ± 4 ,6 0,02 394 ±7.1 ns 395 ± 4 .5 ns
Day 2 post 403 ± 7 ,8 ns 400 ± 7 ,5 ns 395 ±9,4 ns 400 ± 4 ,7 ns
Day 7 post 400±6 .2 ns 399 ± 5 ,3 0.05 395 ± 6.1 ns 401 ± 5 ,8 ns

PEP, (msec)
Contml day 105 ± 4,8 — 101 ±2.6 — 105±6,4 — 105 ±4.3 —
Day 1 103 ± 4,5 ns IO4± 3.6 ns 103 ±4.7 ns 105 ± 4,3 ns
Day 2 106 ± 5,0 ns 104 ± 3.4 ns IOO±5.2 ns IOO± 4,8 0.04
Day 3 109 ± 3.8 ns 107 ± 4,2 ns 101 ±5.4 ns 100± 4.3 0.02
Day 4 II4± 6.0 ns 103 ± 3.2 ns 103 ±5.5 tis 95 ± 4,7 0.02
Day 7 105 ± 4.8 ns iO4± 3,8 ns IO5±5,8 ns 96 ± 2,3 ns
Day 1 post 105 ± 5.0 ns 104± 3,8 ns 103 ±5.6 ns 94 ± 2,5 0.02
Day 2 post 105 ± 5.8 ns 104 ± 3,6 ns 104 ±7.3 ns 98 ± 2,1 0,03
Day 7 post 108 ± 5,1 ns 104 ± 3,2 ns IO4±5,6 ns 105 ± 4.4 ns

LVET, (msec)
Control day 296 ± 4.0 ^ 290 ± 2,3 — 290 ±4.2 — 286 ± 3.7 —
Day 1 2 % ± 2.1 ns 299 ± 3,7 0,02 291 ±!,7 ns 285 ± 4,3 ns
Day 2 299 ± 3-3 ns 299 ± 2,5 0.02 288 ±2,5 ns 295 ± 2,8 ns
Day 3 296 ± 3,6 ns 297 ± 4,6 ns 287±2.2 ns 293 ± 2,8 ns
Day 4 298 ± 2,9 ns 296 ± 4.5 ns 288 ±4.0 ns 300 ± 3,2 0.05
Day 7 304 + 4,2 0,03 301 ± 2,9 0,02 287 ±1,9 ns 305 ± 2,4 0.02
Day I post 300 ± 4.1 ns 300 ± 4,2 0,02 291 ±3.3 ns 302 ± 3.8 ns
Day 2 post 299 ± 3,4 ns 297 ± 5,2 ns 29i ±4,6 ns 302 ± 4.6 0.03
Day 7 post 298 ± 8.1 ns 295 ± 3,9 ns 290 ±2,5 ns 292 ± 4.8 ns

PEP,/LVET
Control day 0 36:1:0,017 — 0,35:1:0,010 — 0,36 ±0,022 — 0.37 itO,O12 —
Djy 1 0.35 ±0,018 ns 0,35:10.013 ns 0,36±0,017 ns 0.37±0,015 ns
Day 2 0.36:t0,019 ns 0.35:10.013 ns O,35±O.OI9 ns 0,34:1:0,017 0,02
Day 3 0,37:1:0,015 ns 0.36:tO,OI4 ns 0.35 ±0.019 ns 0,34:tO,OI5 0,04
Day 4 0,38:to,021 ns 0,35:10,011 ns O36±O,OI9 ns 0,32:1:0,016 0,02
Day 7 0,35:tO.OI6 ns 0,34:to,013 ns 0,36±0,021 ns 0,31 ±0.009 0.03
Day 1 post 0,35:tO,OI8 ns 0,35:!:0,015 ns 0,35±0,019 ns 0,31 =to.oio 0.03
Day 2 post 0.35:tO.OI8 ns 0,35:to,010 ns 0,36 ±0,025 ns 0,32:to.oio 0.03
Day 7 post 0,36:10,017 ns 0.35:t O . O l l ns 0,36 ±0,020 ns 0,36:10.009 ns
QS; = total electromechanical systole; PEP ^ Preejectlon period; LVET = left ventricular ejection time,
* p-values. Wilcoxon matched-pairs signed-ranks test versus control day (2-tai!ed probability; ns = not significant)
 De Cr^e—Hemodynamic Effects of Nebivolol 101
ATENOLOL PROPRANOLOL

.40

.38

,36
i
.34

.32

.30

.28
0 1 DAYS

PINDOLOL NEBIVOLOL

.40

.38

.36

.34

.32

.30

.2B
0 t ' DAYS ' DAVS

FIG. 1. Mean values ± SE of the ratio PEP,/LVET, of the systolic lime intervals on a control day, before daily
administration on days I, 2, 3, 4, and 7 during treatment ( ): and after discontinuation of treatment ( ) with atenoiol
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 PEP, 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 PEP,/LVET, 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 LVET, during treatment with the different
p-adrenergic antagonists are depicted in Figure 3. The shortening of the postexercise LVET,,
observed in control conditions, was significantly inhibited during treatment with atenolol,
propranolol, and pindoloi. 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 LVET,
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 the very small number of volunteers involved in these series of experiments, it is
noteworthy that the control values of all hemodynamic parameters were comparable and not
102 Angiology—77i^ Journal of Vascular Diseases February 1990
PEPc
PINDOLOL NEBIVOLOL

II
ttc
10*
loa

9C

e;
BC
4 r I 3

LVETc
PINDOLOL NEBIVOLOL
JIIV-

30C

29;
290
28!

Zti-
27C
Fiti. 2. Mean values ± SE of
preejeclion period (PEP.), left ven-
tricular ejection time (LVET,), and the
PEPc/LVETc ratio PEP,/LVET, of the systolic time
NEBIVOLOL
PINDOLOL intervals on a control day: 3 hours
after daily administration ( ) of pin-
dolol or 6 hours after daily administra-
tion ( ) of nebivolol on days I, 4,
and 7; and on days 1, 2, and 7 after
discontinuation ( ) of treatment
with pindolol or nebivolol in 7 volun-
teers. * p-values. Wilcoxon matched-
pairs, signed-ranks test versus control
day (2-taiied probability); * p < 0.05.

significantly different for each of the four sessions. Furthermore, seven days after discontinu-
ation 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 volun-
teers.'' 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 p-adrenergic
antagonists tested. Indeed nebivolol 5 mg od lowered peak exercise heart rate and systolic
blood pressure by \59c and 17% respectively, atenolol 100 mg od by 239^f and 209c. 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
 De Cree—Hemodynamic Effects of Nebivolol 103
PROPRANOLOL
C 1 « 7 1 3 7

PINDOLOL NEBIVOLOL
BC C 1 * 7 1 7

10 X
20
1
M •
1
40
1
•

-L
50
1
fin

FIG, 3. Mean values ± SE of Ihe exercise-induced shortening of the LVEX on a control day (C); 3 hours after daily
administration (v/z/y/z/A^ of pindoloi or 6 hours after daily administration ( ^ ^ ^ ) of atenolol. propranolol. and nebivolol on
days I. 4. and 7; and on days 1. 2, and 7 after discontinualion li i) til irealmcnl in 7 volunteers, '-' p-values, Wilcoxon
matched-pairs, signed-ranks test versus conlrol day (2-t:iiled probability).

systolic and diastolic blood pressure at rest was more pronounced with nebivolol than with
the other p-adrenergic antagonists tested.
A progressive and sustained decrease of the PEP,/LVEX iit rest was observed during
treatment with nebivolol. The lowering of the ratio PEPyLVET, is a valuable index of the
improvement of overall left ventricular function.^' This lowering was the result of a marked
and significant shortening of the PEP, 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 QS:,, might be interpreted as due to an increase of preload
and improved left ventricular compliance."' On the other hand the lengthening of the LVET,
is suggestive of an increased stroke volume, due to a reduction of afterload.' " 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 radionuc-
lide angiocardiography as an index of left ventricular function.^
These beneficial effects on cardiac function were not observed with the other (i-adrenergic
antagonists tested whether or not secondary properties of pi selectivity or intrinsic sym-
pathomimetic activity were involved. Only a transient improvement of cardiac function was
observed with pindolol, due probably to a temporary reduction of afterload mediated through
j32-antagonism. During prolonged treatment with pindolol, however, the ^-blocking effects
104 \ngio\ogy—The Journal of Vascular Diseases February 1990
rather than the intrinsic sympathomimetic activity appeared to predominate, so that all benefi-
cial effects on cardiac performance were lost. Furthermore the shortening of the postexercise
LVET,, which is the expression of the intrinsic positive inotropy of exercise,'^'^ 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'"^
and during treatment with classical p-adrenergic antagonists' and is considered to be indicative
of diminished myocardial contraction.'" "* Therefore, the shortening of the postexercise LVET,
observed during treatment with nebivolol suggests that cardiac function remains optimally
preserved during exercise.
Lastly nebivolo! appears to be a potent pl-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 discon-
tinuation 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 p-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
block p-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 p-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 ^-blocking properties.

Conclusions
Although the precise mechanism of action is not yet elucidated, nebivolol appears to be a
potent and long-acting, selective pl-adrenergic antagonist, with an intriguing hemodynamic
profile, improving left ventricular function at rest and offsetting the negative influence of
classical p-blockade on myocardial contractility during exercise.

Acknowledgmenr
We are indebted to An Baisier for statistical evaluation and for her help in preparing the
figures.
J. De Cree, M.D. ELC.A.
Clinical Research Unit St. Bartholomeus
Jan Palfijn Hospital
Long Bremstraat 70
B-2060 Merksem, Belgium
 De Cr^^—Hemodynamic Effects of Nebivolol
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