Herz-Kreislauf-Therapeutika · Kardiaka · Koronar-Therapeutika

Cardiac Drugs · Cardiac Stimulants · Coronary Drugs

Effect of Amlodipine on Blood Pressure Responses in

Local and Whole-body Cooling in Normotensive Men
b a c
Tuula Tähtinena, Silja Määttäa, Hannu Rintamäki , Hannu Virokannas , and Sirkka Keinänen-Kiukaanniemi

Heruntergeladen von: Chinese University of Hong Kong. Urheberrechtlich geschützt.

Department of Public Health Science and General Practice (Head: Prof. Sirkka Keinänen-Kiukaanniemi),
a b
University of Oulua, Oulu Regional Institute of Occupational Health , Department of Public Health Science
c
and General Practice, University of Oulu , Oulu (Finland)

Summary

The objective of this study was to determine the ability of amlodipine (CAS 88150-42-9,
Norvasc®) to affect the cold-induced rise of blood pressure and heart rate in normotensive
men. Fourteen normotensive men underwent a one-hand cold pressor test (+ 10°C, 5 min)
and a whole-body cold air exposure test (+ 5°C, 45 min) in a crossover study with and without
amlodipine at a seven-day interval.
Amlodipine decreased the levels of initial systolic and diastolic blood pressure before both
tests, but it had no influence on heart rate. During the cold pressor test, amlodipine lowered
the peak diastolic pressure from 96 ± 10 mmHg (mean ± SD) to 92 ± 10 mmHg (p = 0.024).
The rise of diastolic blood pressure was 13 ± 7 mmHg with amlodipine and 16 ± 8 mmHg
without amlodipine (p = 0.138). During the whole-body cold air exposure test, amlodipine
decreased the systolic pressure from 135 ± 2 mmHg to 133 ± 3 mmHg (p = 0.008) and the
diastolic pressure from 88 ± 2 mmHg to 86 ± 1 mmHg (p = 0.005). However, the cold-induced
rise of blood pressure in whole-body cooling was not affected by amlodipine, because it also
decreased the initial values. Amlodipine did not affect the initial or cold-induced changes of
heart rate in these tests.
In conclusion, in normotensive men amlodipine lowers the peak of diastolic blood pressure
in a cold pressor test. In whole-body cold air exposure, amlodipine slightly decreases the levels
of both systolic and diastolic pressures, but has no effect on the cold-induced rise of blood
pressure. Amlodipine does not prevent the cold-induced physiological responses of blood pres-
sure or heart rate.

Zusammenfassung

Wirkung von Amlodipin auf Blutdruckreaktionen bei lokaler Kühlung und Gesamtkörper-
kühlung bei normotensiven Männern
Das Ziel dieser Untersuchung ist der Nachweis der Fähigkeit von Amlodipin (CAS 88150-42-
9 Norvasc®), den kälteinduzierten Anstieg des Blutdrucks und der Herzfrequenz bei normo-
tensiven Männern zu beeinflussen. Vierzehn normotensive Manner unterzogen sich in einer
Crossover-Untersuchung in einem Interval1 von 7 Tagen einem Einarm-Kälte-Blutdrucktest
(+ 10°C, 5 min) und einem Gesamtkörper-Kaltluft-Expositionstest (+ 5°C, 45 min) mit und
ohne Verabreichung von Amlodipin.
Amlodipin verringerte vor beiden Tests die Niveaus der anfänglichen systolischen und diastoli-
schen Blutdrücke, hatte aber keinen Einfluß auf die Herzfrequenz. Während des Kälte-Blut-
drucktests verringerte Amlodipin die diastolischen Spitzenwerte von 96 ± 10 mmHg (Durch-
schnitt ± Standardabweichung) auf 92 ± 10 mmHg (p = 0,024). Die Erhöhung der diastoli-
schen Blutdrücke betrug 13 ± 7 mmHg mit Amlodipin und 16 ± 8 mmHg ohne Amlodipin
(p = 0,138). Während des Gesamtkörper-Kaltluft-Expositionstests verringerte Amlodipin den
systolischen Druck von 135 ± 2 mmHg auf 133 ± 3 mmHg (p = 0,008) und den diastolischen
Druck von 88 ± 2 mmHg auf 86 ± 1 mmHg (p = 0,005).
Arzneim.-Forsch./Drug Res. 49 (I), Nr. 6 (1999)
494 Tähtinen et al. - Amlodipine
 Die durch die Kälte induzierte Erhöhung des Blutdruckes bei der Gesamtkörper-Abkühlung
wurde jedoch durch Amlopidin nicht beeinflußt, da es auch die Anfangswerte verringerte.
Amlopidin hat in diesen Tests keinen Einfluß auf die anfänglichen oder die kälteinduzierten
Veränderungen der Herzfrequenzen.
Zusammenfassend kann man feststellen, daß Amlopidin in den Kälte-Blutdrucktests die Spit-
zenwerte der diastolischen Blutdrücke bei normotensiven Männern verringerte. Bei der Ge-
samtkörper-Kaltluft-Exposition verringerte Amlodipin die Niveaus sowohl der systolischen
als such der diastolischen Blutdrücke ein wenig, beeinflußte aber den kälteinduzierten Blut-
druckanstieg nicht. Amlopidin verhindert die kälteinduzierte physiologischen Reaktionen des
Blutdruckes oder der Herzfrequenz nicht.

Key words Amlodipine · Calcium channel blocker, dihydropyridine 4 CAS 88150-42-9 · Nor-
vasc®, blood pressure, cold pressure test, man, temperature, whole-body exposure

Arzneim.-Forsch./Drug Res. 49 (I), 494-499 ( 1999)

Heruntergeladen von: Chinese University of Hong Kong. Urheberrechtlich geschützt.

1. Introduction cold-induced peripheral vasoconstriction and rise
Cooling of the human body stimulates the peri- of blood pressure. There are no published data
pheral thermoreceptors in the skin. The sensory concerning the effect of amlodipine in cold.
nerves mediate the information from the receptors Some epidemiologic studies have shown that sys-
to the central nervous system. When the temper- tolic and diastolic blood pressures are higher dur-
ature regulation Center in the hypothalamus re- ing the cold season than the warm season [9]. In
ceives information of cold, it activates the efferent the countries with a cold climate, such as Finland,
sympathetic nervous system. The sympathetic ef- all people are exposed to cold air when they are
fects are mediated by norepinephrine [11]. The ac- outdoors during the cold season. In addition,
tivation of the sympathetic nervous system results people who work outdoors or in artificially refri-
in peripheral vasoconstriction, a rise of blood pres- gerated working facilities, such as cold stores, are
sure and an increased heart rate [2]. There are no exposed to cold air throughout their working
known vasodilator nerve fibers in the cutaneous hours. Clothing decreases the surface area directly
vessels, and vasodilatation is brought about by de- exposed to cold and creates a more favourable mi-
creasing constrictor tone [1], although active cuta- croclimate.
neous vasodilation has also been suggested [3]. Many people with cardiovascular diseases live in
Generally, cold exposure elevates blood pressure. countries with a cold climate or work in cold
Different types of exposure to cold produce differ- places. Antihypertensive or cardiac medication
ent responses in blood pressure, peripheral circula- should normalize their high blood pressure or
tion and heart rate. A cold pressor test elevates maintain normotension in both warm and cold en-
blood pressure and heart rate [4]. Exposure of the vironments. On the other hand, antihypertensive
face to cold air results in a rise of blood pressure medication should not prevent the normal cold-
and bradycardia [5, 6]. Whole-body exposure to induced peripheral vasoconstriction and increase
cold air leads to a rise-in blood pressure-[7], while in heart rate, which minimize heat loss and prevent
the heart rate may increase, decrease or remain whole-body cooling.
constant, depending on the degree and rate of The purpose of this study was to investigate, in
body cooling and the exposure time [2]. normotensive healthy men, whether amlodipine af-
Amlodipine (CAS 88150-42-9) is a blood vessel se- fects the cold-induced physiological blood pressure
lective dihydropyridine calcium channel blocker and heart rate responses. In addition, the differ-
with a distinctively long elimination half-life 35- ences in the responses to cold pressor and whole-
45 h, and the indications for it are hypertension, body cold air exposure tests were compared.
angina pectoris and cardiac insufficiency. Amlodi-
pine acts primarily by inhibiting the extracellular
calcium influx through the vascular smooth muscle 2. Subjects, material and methods
cell membranes. The antihypertensive action of
amlodipine is related to its direct relaxant effect on 2.1. Subjects
vascular smooth muscle, which leads to dilation of Fourteen healthy normotensive male medical students
both arteries and arterioles. This, in turn, leads to served as voluntary test subjects. The study protocol was
a reduction in total peripheral resistance and re- approved by the Ethics Committee of the Medical Fac-
ductions in systolic and diastolic blood pressure, ulty at the University of Oulu. The participants were
informed about the study and asked to give written con-
generally without reflex tachycardia and without sent.
postural hypotension [8]. The actions of amlodip- The tests were made between January 31 and March 1,
ine are not mediated via the sympathetic nervous 1995. Two or three participants at a time attended the
system. Consequently - at least in-theory - the va- test at 8 a.m. after a normal breakfast. No smoking or
sodilating action of am lodipine could prevent the coffee were allowed in the morning before the test. Dur-
Arzneim.-Forsch./Drug Res. 49 (I), Nr. 6 (1999)
Tähtinen et al. - Amlodipine 495
ing the 2 weeks before the experiments the subjects had diastolic blood pressure and heart rate measured in the
had no infections. The previous evening and night had cold climatic chamber were recorded as the results of the
been normal. climatic chamber test.

2.2. Study design 2.4. Statistics

Every subject participated twice in the same crossover
test study procedure, with a one-week interval between
the two trial periods. Seven randomly selected particip-
ants ingested 5 mg of amlodipine1) at 8 a.m. 49 and 25 h
before the trial and on the morning of each day of the
trial. One week later the trial was repeated without prior
ingestion of amlodipine. Seven participants did not take
amlodipine before the first trial, but ingested 5 mg amlo-
dipine 49, 25 and 1 h before the second trial one week
later.
Each trial session took 3.5-4.0 h. At the beginning of
the trial, the subjects wearing their normal indoor
clothes sat on a chair with minimal movement and talk
for 30 min at a room temperature of + 21 °C. After this
adaptation time, each participant immersed his right
Statistical analyses were conducted with the SPSS for
Windows 5.0 software of the University of Oulu. The
results are given as means ± standard deviation (SD).
After controlling for normality of distributions of vari-
ables, Student’s two-tailed paired t-test was used to com-
pare the values of the same subjects with or without am-
lodipine.
3. Results
3.1. Basic characteristics
All 14 participants were healthy male medical stu-
dents aged 20-30 years (23 ± 3 years, mean ± 2SD).

Heruntergeladen von: Chinese University of Hong Kong. Urheberrechtlich geschützt.

hand up to the wrist into stirred cold water (+ 10.0 ± Their mean body mass index was 23 ± 2 kg/m and
0.5 °C) and held the hand in the water for 5 min without mean fat percentage 14 ± 3%.
any movement or talk.
After the cold pressure test, the subjects undressed to
shorts, and their height, weight and skin fold thickness 3.2. Cold pressor test and blood pressure
were measured. Thereafter, the subjects walked calmly In the cold pressor test, the initial systolic and dia-
into a warm climatic chamber (+ 27 °C, velocity of air stolic blood pressures were lower with amlodipine
< 0.2 m/s and relative humidity of air 30%) nearby and than without it (Table 1, Fig. 1). As a response to
sat there on a chair without any movement or talk, lis- cold, systolic and diastolic blood pressures in-
tening to neutral music from earphones for 45 min. creased and the peak values were achieved in 1.4-
After this stabilizing period, the test subjects walked
slowly into the cold climatic chamber in the next room 2.0 min after the start of cold water immersion.
(+ 5 °C, air velocity < 0.2 m/s, relative humidity 50%) Amlodipine decreased both the rise and the peak
and sat there for 45 min the same way as in the first values of diastolic blood pressure. However, only
chamber. the decrease in the peak diastolic blood pressure
during the cold pressor test was statistically signifi-
2.3. Measurements
cant (p = 0.024).
Height was measured with a calibrated vardstick and
weight with a calibrated scale (Mettler-ID 1 -Multirange,
Mettler Co., Switzerland). Body mass index was calcu-
lated as weight (kg) divided by height squared (m2). Skin
fold thickness was measured by Harpenden caliper from
the biceps, triceps, subscapularis and suprailiacal regions
and the fat percentage was calculated [10]. The blood
pressure and heart rate measurements were installed by a
computer and performed oscillometrically from the left
upper arm using an indirect ambulatory blood pressure
monitor (Meditech ABPM-02, Meditech Co., Budapest,
Hungary). Automatic measurements were made every 5
min during all the procedures and, in addition, once a
minute during the cold pressor test manually by pressing
a button.
In the cold pressor test, the initial blood pressure and
heart rate before immersion were calculated from 5 val-
ues measured before the test. The lowest and highest val-
ues were excluded, and the mean of the remaining 3
measurements was used as the initial value. The peak
values and the rise of systolic and diastolic blood pres-
sures and heart rate during the immersion were recorded
as the effects of the cold pressor test.
In the whole-body cold exposure test, systolic and dia-
stolic blood pressures and heart rate were calculated as
means of the last nine measurements during the 45 min
exposure to + 27 °C and + 5 °C in climatic chambers.
The difference between the means measured in the two
climatic chambers and the peak values of systolic and

1)
Norvasc ®; manufacturer: Pfizer Co., Espoo (Finland).
Arzneim.-Forsch./Drug Res. 49 (I), Nr. 6 (1999)
496 Tähtinen et al. - Amlodipine

3.3. Whole-body cold air exposure test and blood
pressure
In the whole-body cold air exposure test, amlodi-
pine decreased the initial mean systolic and dia-
stolic blood pressures in the warm and cold cli-
matic chambers statistically significantly (Table 2,
Fig. 2). As a response to cold exposure, the peak
values of systolic and diastolic pressures were
achieved in 22.5-30.5 min after the beginning of
the exposure.
Amlodipine decreased the peak values of systolic
and distolic pressures. However, the magnitude of
the rise in systolic blood pressure induced by cold
was not altered by amlodipine and the rise in dia-
stolic pressure was greater with than without amlo-
dipine.
Arzneim. -Forsch ./Drug Res. 49 (I), Nr. 6 (1999)
Tähtinen et al. - Amlodipine
Heruntergeladen von: Chinese University of Hong Kong. Urheberrechtlich geschützt.
3.4. Heart rate
Amlodipine did not affect significantly the initial
levels and cold-induced responses of heart rate
(Table 1 and 2). The heart rate values rose at the
beginning of the cold pressure test (Table 1) and
decreased during the whole-body cold exposure
test (Table 2).
35 Adverse reactions
One participant discontinued the cold pressor test
with amlodipine after 4.5 min of hand immersion
because of precollapse. His blood pressure at 4 min
was 77/53 mmHg and heart rate 36 beats/min. The
values of this participant are included in the re-
sults, with the exception that his values at 5 min in
the cold pressor test are missing.
497
4. Discussion
The present study demonstrates that amlodipine
slightly decreases the levels of both systolic and
diastolic blood pressures during cold pressor and
whole-body cold air exposure tests, but it does not
prevent the cold-induced rise of blood pressure or
the heart rate response.
A cold pressor test measures the function of the
autonomous nervous system. If it is healthy, the
responses manifested as changes in blood pressure
and heart rate are most marked during the first 2
min of the cold pressor test [4]. In the present
study, the sudden temperature drop from + 21 °C
air to + 10 °C water was a very strong local stimu-
lus to the skin of the right hand, which constitutes
about 2.5 % of the whole body surface area. The
rises of both blood pressures and heart rate were
most marked during the first 2 min after the begin-
ning of the cold pressor test. Thereafter, the blood
pressures and heart rate declined nearly to the ini-
tial values in 5 min. Consequently, the test was
properly performed.
Previously it has been shown that a non-selective
dihydropyridine calcium channel blocker, nifedip-
ine, decreased the peak values of systolic blood
pressure in coronary artery disease patients in a
cold pressor test [11]. Felodipine and isradipine are
blood vessel selective dihydropyridine calcium
channel blockers with elimination half-lives of 25
and 8 h, respectively. Medication for 4 weeks with
felodipine [12] and 6 weeks with isradipine [13] de-
creased the systolic and diastolic blood pressures
of hypertensive patients in cold pressor tests. The
rise of blood pressure induced by cold was lower
after 6 weeks of medication with isradipine than
without medication [13].
Apart from the fact that we used a different cal-
cium channel blocker, there were also other differ-
ences between designs of the previous studies and
the present study. Our subjects were normotensive
healthy men, the duration of medication with am-
lodipine was two days before the test, and the
whole-body cold air exposure was performed dur-
ing the same visit as the cold pressor test. At any
rate, anyhow, the blood pressure responses with
amlodipine in our cold pressor test were approxim-
ately similar to those obtained with other calcium
channel blockers previously.
Whole-body exposure to cold air leads to a rise in
blood pressure [7], during which the heart rate may
increase, decrease or remain unchanged, depending
on the degree of body cooling and the cold air
exposure time [2]. During a whole-body cold air
exposure, cooling affects the whole surface area of
the body, increases the activity of the sympathetic
nervous system and results in general peripheral
vasoconstriction. During the 45 min whole-body
cold air exposure the cooling of the body takes
place slowly and resembles the circumstances actu-
ally present in many cold surroundings as shown
in the studies of Oksa [14] performed in the same
climatic chamber as this study.
In the present study, the rises of both systolic and
diastolic blood pressure were rapid and began dur-
498
ing the first 5 min of cold exposure. Both blood
pressures persisted high until the end of the whole-
body cold exposure of 45 min. This reaction does
not suggest any adaptation and, apparently, gen-
era1 and peripheral vasocontriction continued
throughout the cold exposure time. The heart rate
decreased slowly throughout the cold air exposure
time of 45 min. This reaction suggests that con-
tinuous peripheral vasocontriction increases the
central blood volume. The heart tries to maintain
the central circulation at an equilibrium and the
heart rate decreases.
There are only a few studies demonstrating the
effects of antihypertensive medication in cold air
exposure and none with calcium channel blockers.
The beta-blockers propranolol and atenonol
raised diastolic blood pressure and total peri-
pheral resistance in cold air exposure at 5 °C for
1 h, but had little effect on the mean arterial pres-
Heruntergeladen von: Chinese University of Hong Kong. Urheberrechtlich geschützt.
sure compared to placebo [15]. In another study,
propranolol failed to lower the increased blood
pressure caused by cold air exposure [16]. In the
present study, amlodipine decreased systolic and
diastolic blood pressures both before and during
cold air exposure. Despite this, amlodipine did
not prevent the cold air induced rise of systolic
and distolic blood pressures and it did not affect
the heart rate.
The subjects in our study were healthy non-obese
men, and their sensory nerves, sympathetic nerv-
ous systems and the blood vessel walls therefore
responded normally to the cold stimulus. We
wanted to find out how amlodipine amects healthy
men in cold. The antihypertensive effect to amlodi-
pine is caused by vasodilation of arteries and ar-
terioles without reflex tachycardia. Strong peri-
pheral vasodilation without reflex tachycardia
could lead to a marked drop in blood pressure, col-
lapse and increased heat loss from the skin in cold
environment. One of our subjects precollapsed in
the cold pressor test after ingestion of amlodipine.
The reason for this precollapse may have been a
vasovagal reaction. It is possible that amlodipine
attenuated the cold-induced rise of blood pressure
and heart rate too much in this normotensive sub-
ject.
In conclusion, amlodipine given to normotensive
men did not prevent the cold-induced physiological
responses of blood pressure and heart rate. Conse-
quently, amlodipine could be considered a suitable
cardiovascular drug for a patient exposed to cold,
but the effects on cardiovascular patients remain
to be elucidated.
5. Literature
[1] Zelis, R., Am. J. Med. 27, 3 (1983)
[2] Granberg, P.-O., Arct. Med. Res. 50 (Suppl. 6), 23
(1991)
[3] Sanders, J. S., Mark, A. L., Ferguson, D. W., Circula-
tion 79, 815 (1989)
[4] Benetos, A., Safar, M. E., Am. J. Hypertens. 4, 627
(1991)
[5] LeBlanc, J., Blais, B., Barabe, B. et al., J. Appl. Phy-
siol. 40, 127 (1976)
Arzneim.-Forsch./Drug Res. 49 (I), Nr. 6 (1999)
Tähtinen et al. - Amlodipine
[6] Kilgour, R. D., Carvalho, J., Can. J. Physiol. Pharma-
col. 72, 1193 (1994)
[7] Raven, P., Niki, I., Dahms, T. et al., J. App. Physiol.
29, 417 (1970)
[8] Haria, M., Wagstaff, A., Drugs 50, 560 (1995)
[9] Näyhä, S., Scand. J. Prim. Health Care 3, 99 (1985)
[10] Durnin, J. V. G. A., Rahaman, M. M., Br. J. Nutr.
21, 544 (1967)
[11] Goldhaber, S. Z., White, H. D., Holman, B. L., J.
Am. Coll. Cardiol. 1, 1512 (1983)
[12] Fariello, R., Boni, E., Corda, L., Am. J. Hypertens.
4, 27 (1991)
[13] Duprez, D., De Backer, T., De Pue, N., Am. J. Hy-
pertens. 4, 194 (199 1)
[14] Oksa, J., Cooling and neuromuscular performance
in man, Doctoral thesis, Studies in sport, physical educa-
tion and health No. 53, University of Jyväskylä, Fin-
land (1998)
Arzneim.-Forsch./Drug Res. 49 (I), Nr. 6 (1999)
Hirata et al. - Toborinone
[15] Headley, S. A., Moser, C. D., Golan, R. et al., Can.
J. Physiol. Pharmacol. 74, 112 (1996)
[16] Reed, H. L., Kowalski, K. R., D’Alesandro, M. M.,
Aviat. Space Environ. Med. 62, 111 ( 1991)
Acknowledgements
The authors appreciate the contributions of the 14 med-
ical students who participated in this study. The authors
thank Pfizer Medical Finland for financial support to
this study.
Correspondence: Dr. Tuula Tähtinen MD, Department
of Public Health Science and General Practice, Univer-
sity of Oulu, Aapistie 1, SF-90220 Oulu (Finland)
E-mail: tuula.tahtinen@oulu.fi
Heruntergeladen von: Chinese University of Hong Kong. Urheberrechtlich geschützt.
499