537

Symposium

The Effects of Verapamil SR and Bisoprolol on

Reducing the Sympathetic Nervous System's Activit y
Ningling SUN, Tingting HONG , Ruijun ZHANG *, and Xuan YANG*

To assess the response of the sympathetic nervous system (SNS) to the handgrip test in essential
hypertensive patients and to evaluate the effects of verapamil SR and bisoprolol on the reduction of the
SNS's activity. Seventy eight essential hypertensive patients (50 receiving verapamil SR treatment and 28
receiving bisoprolol treatment) took the handgrip test while the SBP, DBP, and HR were measured on
three occasions during the test (before test, 3 min after the patients squeezed the handgrip, and 2 min af-
ter the handgrip was released). Before and after the patients received Verapamil SR or Bisoprolol treat-
ment, the plasma concentrations of epinephrine(E), norepinephrine (NE), angiotensin-II (All), aldosterone
(ALD), endothelin-1 (ET-1) and renin activity (RA) were measured post-test. 1) In about 70% of the essen-
tial hypertensive patients, SNS activity was above normal. Their HR and BP exceeded 20% when respond-
ing to stress. 2) In these patients, the baseline plasma concentrations of E, NE, All, ET-1, ALD, and RA
were higher than those whose SNS's activity was normal. 3) After 6 weeks of treatment, all the patients'
BPs decreased remarkably. Verapamil SR could reduce the plasma concentrations of NE, All, and ET-1 and
increase RA. Bisoprolol could reduce E and RA. These two antihypertension drugs can both decrease BP
and reduce the activity of SNS through different mechanisms. (Hypertens Res 2000; 23: 537-540)

Key Words: hypertension, sympathetic nervous activity, verapamil SR, bisoprolol

channel blocker - Verapamil SR or the R receptor block-

er bisoprolol which was applied to the subjects, definitely
Introduction encouraged us to assess the different efficiency of the two
Authoritative researchers have asserted that the auto- antihypertensive agents. In other words, the handgrip test
nomic systems of patients with a risk of hypertension react was used as a tool to study the effects of the two anti-
in a unique way to emotional stress, thereby demonstrat- hypertensive drugs on the cardiovascular and neuro-
ing a psychophysiological neurovegetative hyperdysreac- vegetative systems.
tivity. The plasma concentrations of catecholamine,
Angiotensin-II (All), and endothelin (ET-1) are strong
Subjects and Methods
indicators of the state of the sympathetic nervous system.
Hypertensive patients react to stimuli such as the cold
Subjects
pressor test (immersion of a limb in ice water for 1 min)
and the handgrip test (isometric contraction at 30% of the Seventy-eight essential hypertensive patients were re-
maximum individual contractile capacity) with a higher cruited from our hospital outpatient clinics or infirmary
significant cardiovascular response (1). This response was during a one-year period (Feb. 1998-Feb. 1999). The pa-
studied through the handgrip test in our research. Further- tients were allocated to one of two treatment groups
more, pharmacological therapy employing a calcium (starting with verapamil SR or bisoprolol ). Group A, 50

From the Cardiovascular Department, Peking University, People's Hospital, Beijing, P.R.China and *Department of Cardiology, Shan-
dong Qilu Shihua Center Hospital, Zibo, P.R.China.
Address for Reprints: Sun Ningling, M.D., Cardiovascular Department, Peking University, People's Hospital, Beijing 100044, P.R.China.
Received December 6, 1999; Accepted in revised form March 23, 2000.
538 Hypertens Res Vol. 23, No. 5 (2000)

patients (26 males, 24 females), aged 30-68 (an average ET-1 Measurement
of 56.2±8.2), received the verapamil SR treatment. The On the same occasions, we drew 2 pl of venous blood for
other 28 patients (16 males and 12 females), aged 32-62 ET-1 measurement. As soon as the samples were taken
(an average of 52.6±8.2) took bisoprolol as Group B. All from the vein, they were mixed with 10% EDTA and
patients suffering from secondary hypertension were ex- aprotinin, each at 50 ,ul. They were then centrifuged be-
cluded. After an initial physical examination, the anti- low 4°C for 15 min at a speed of 3,000 cycles per minute.
hypertensive medication was discontinued one week be- The variance was 5% in batch and <10% among batches.
fore the study. Hypertension was defined as systolic blood
pressure (SBP) higher than 140 mmHg and diastolic Administration Design
blood pressure (DBP) higher than 90 mmHg on three Verapamil SR, which was provided by Knoll Phar-
occasions during the week before the study. The study maceuticals (Batch No. 784), was given at 240 mg daily.
was approved by the institutional ethical committee and On the other hand, bisoprolol, which was supplied by
the subjects gave informed consent. Merk Pharmaceuticals (Batch No. 12635 059), was given
at 5 mg daily. Both of the two drugs were administered
for six weeks. Throughout the study, the patients were
Protocol
closely followed up and took the handgrip test before and
Blood Pressure Measurement and Handgrip Test after the treatment.
At each visit, which was arranged between 8 and 10 AM,
the same arm of the patient (rather than the one the pa-
Statistical Analysis
tient chose to grip with) should be used for the blood
pressure measurements in a sitting position. The handgrip Data was expressed as mean±SD. The change in each
test was conducted by using a Martin Vigorimeter. After parameter from pre- to post-stress was analyzed within
a 30-min rest, blood pressure and heart rate were meas- groups using paired tests. Such change was compared be-
ured and recorded as pre-grip measurements. The same tween the two different SNS's activation types using
measurements were then taken when the patients Fisher's exact test when the variance was regular or the
squeezed the handgrip continously for 3 min using 30% of rank sum test when it was not. A p value of less than
his/her maximum strength. Two minutes after the patient 0.05 was considered statistically significant. All the cal-
had stopped the handgrip test, his/her blood pressure and culations were executed using GPIS software on comput-
heart rate were measured again and recorded as post-grip ers.
measurements.

Results
Measurement of Plasma CA Concentration
Seven microliters of venous blood for catecholamine 1. Before treatment, the handgrips could induce an in-
measurements were drawn into a polypropylene syringe crease of blood pressure and heart rate. In Group A, 35
during the pre-grip and post-grip tests before the patient patients' (about 70%) BP and HR exceeded more than
had taken any antihypertensive drugs and during the post- 20% of the baseline values from pre- to post-stress. So did
grip test six weeks after the patient had received medica- 20 patients (about 71%) in Group B. Therefore, nearly
tion. The blood samples were immediately mixed with 70% of the hypertensive patients in the study experienced
2% EDTA and centrifuged at 4°C for 20 min at a velocity hyperdysreactivity to stress while the other 30% of the
of 2,500 cycles per minute. The plasmas were frozen at patients were determined as normal (Table 1).
-70°C until the catecholamine measurements were taken 2. After six weeks of antihypertensive treatment, we
within a few weeks. Plasma catecholamines were meas- found that stress could no longer evoke the rise of BP
ured using high performance liquid chromatography and HR in all the patients, regardless of the type of sym-
according to Ma Xueyi as previously reported (2). pathetic activation. This phenomenon possibly suggested
that the two antihypertensive drugs can lower the SNS's
Measurement of Plasma PRA and Angiotensin-11(All) activity while decreasing BP (Table 1). Furthermore, the
Three microliters of blood for PRA and All measure- post-handgrip BP and HR decreased more significantlyin
ments were drawn from a forearm vein on the same three those patients with hyperactivity after treatment. This
occasions mentioned above. The samples were mixed with suggested that the patients who had hyperactivity of SNS
7 nl of 10% EDTA and Oxine Sulpate, and then centri- are more sensitive to the two medications than are others.
fuged at 4°C similar to the CA measurement. Plasma 3. Throughout the study, we determined the plasma con-
PRA and All were measured using a series of test kits centrations of CA, All, PRA, and ET-1. On the basis of
provided by the Beijing Free Bioengineering Co., strictly our observation, we found: (1) Before treatment, there
according to the instructions given. was no significant change of vasoactive substances during
stress. (2) The baseline values of those substances in pa-
Sun et al : The Effects of Verapamil SR and Bisoprolol on Reducing the SNS's Activity 539

tients with hyperdysreactivity were higher than in others.

(3) Both the two drugs could decrease the plasma level of
vascular substances. The difference could be due to Vera-
pamil SR's ability to decrease NE, ET-1, and All, and in-
crease PRA, while Bisoprolol could lower the plasma
levels of E and All (Table 2).

Discussion
Sympathetic activity can be affected by many factors such
as heredity, behavior, and social culture. These factors in-
teract with each other, and in combination they exert a
significant effect on the sympathetic nervous system. Var-
ious studies have demonstrated that sympathetic hyper-
activation in essential hypertension is not rare. Moreover,
other researchers have shown that sympathetic activation
can be triggered by environmental stress through the
baroreceptor (3). The nervous system, which regulates
the cardiocirculatory system, is excited by the handgrip
test. Through medullar-sympathetic centers and pathways,
it stimulates the release of the neurotransmitters (such as
NE and E) and thus increases cardiac output and
peripheral resistance. As a result, the blood pressure in-
creases and the heart rate decreases. According to our ex-
perience, a BP and HR exceed more than 20% of their
baseline values during stress indicates hyperdysreactivity.
The vasoactive substances in the circulation, especially
NE, All and ET-1, can indicate sympathetic reactivity
(4). The higher the plasma levels of NE and All are, the
stronger the sympathetic activity is. In this study, we used
handgrip tests to induce the subjects' sympathetic activa-
tion. As we observed, about 70% of the hypertensive pa-
tients' BP and HR exceeded more than 20% in the peak
of the stress and returned to the baseline level 2 min after
the stress. The sympathetic activities of the other 30% of
the patients were normal. Their BP and HR showed in-
creases of only 8-12% from pre- to post-stress. Further-
more, no subject showed a significant increase in plasma
hormones following the handgrip test. But there were
differences between the two hypertensive types with differ-
ent sympathetic activities. In comparison, the patients
with hyperdysreactivity had higher plasma baseline values
of NE, ET-1, PRA, and All (p<0.01). On the basis of
this data, we can conclude that the rise of the BP and HR
during acute stress is the result of the abnormal regula-
tion of the nervous system, yet a long-run process of re-
sponse to chronic stress will result in high plasma sub-
stance levels. All these indications have led us to a conclu-
sion, nevertheless, that it may be possible that stress is an
important factor in the starting mechanism of hyperten-
sion.
Both of the therapeutic approaches induced a signifi-
cant reduction of the blood pressure and heart rate.
Furthermore, the BP and HR did not increase significant-
ly when the hypertension responded to stress. In addition,
540 Hypertens Res Vol. 23, No. 5 (2000)

Table 2. The Changes of Post-Grip Plasma Concentrations of Cadiovascular Activity Substances from Pre- to Post- Ther-
apy in Two Groups (X± SD)

the plasma levels of the vasoactive substances decreased patients.

remarkably, but they presented different profiles in the In conclusion, verapamil SR should be administrated
two groups. Verapamil SR induced a marked decrease of to those with high plasma levels of NE, All, and ET-1
NE, All, and ET. The possible mechanism might in- and with abnormal sympathetic nerve activities, while
volved the drug blocking the calcium channel, with this bisoprolol should be prescribed to patients with high E
reducing the calcium which is important in releasing and PRA levels. Both of these two antihypertensive drugs
neurotransmitters in nerve cells. These decreases are pre- can reduce sympathetic activation, thereby lowering the
dominantly caused by central effects, presumably in the blood pressure steadily.
nucleus tractus solitarius, resulting in a decrease in sym-
pathetic outflow. In addition, an inhibition of the energy-
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