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Acta Physiol Scand 1989, 136, 463-471

Comparative effects of the a-adrenoceptor agonists


noradrenaline, phenylephrine and clonidine in the
human saphenous vein in vivo and in vitro

T. SJOBERG, L. N O R G R E N , K.-E. ANDERSSON and S. S T E E N


Departments of Surgery and Clinical Pharmacology, Lund University, Sweden

SJOBERG, T., NORGREN, L., ANDERSON, K.-E. & STEEN, S. 1989.Comparative effects of
the a-adrenoceptor agonists noradrenaline, phenylephrine and clonidine in the human
saphenous vein in vivo and in vitro. Acta Physiol Scand 136, 463-471. Received 14
March 1988,accepted 1 5 February 1989.ISSN 0001-6772.Departments of Surgery
and Clinical Pharmacology, Lund University, Sweden.

+
The a-adrenoceptor-mediated contractile effects of noradrenaline (al a,),phenyle-
phrine ( a l )and clonidine (a,) on human saphenous veins were investigated in viva
and in vitro. By infusion (0.3 ml min-I) of the drugs (increasing concentrations in the
infused solution) into distended (40mmHg) saphenous veins in six healthy subjects,
local vasoconstriction was induced, measured by a photo-electric device. The drugs
induced dose-dependent contractions in all subjects, and dose-response curves were
constructed. These were compared with concentration-response curves based on in-vitro
results. Macroscopically normal saphenous veins, taken at saphenousectomies, were
used, and the preparations were contracted isometrically in organ baths by the agonists.
From the curves obtained in vivo and in vitro, the relative potencies of phenylephrine
and clonidine (in relation to noradrenaline) were calculated and compared. The relative
potencies of phenylephrine in vivo (76%) and in vitro (82%) did not differ significantly.
However, the relative potency of clonidine was significantly (P< 0.05) lower in vivo
(90%) than in vitro (99%). Thus, it is concluded that there are differences between the
results obtained in vivo and in vitro, stressing the importance of comparative in ciao-in
vitro studies.

Key words : a,-adrenoceptors, a,-adrenoceptors, clonidine, human, in vitro, in vivo,


noradrenaline, phenylephrine, saphenous veins.

Most studies of a-adrenoceptor function in the direct effects of agonists and antagonists on
blood vessels have been performed in vitro, and human veins in vivo. One approach has been to
it is often unknown if the results are applicable study changes in vessel diameter. For example,
also in vivo, where difficulties in estimating the the local effects of vasoactive substances on
exact drug concentration in the vicinity of the superficial hand veins were studied microscopi-
receptors (Goldstein et al. 1986), interference of cally by Collier et al. (1972). Aellig (1981) used
blood-borne factors (Schumann & Lues 1983), a linear variable differential transformer for
central actions (de Jonge et al. 1982), reflexogenic direct recording of venous compliance at a
compensatory mechanisms (Guyton 1981), etc. constant congesting pressure induced by a
must be taken into consideration. Comparative tourniquet. With a photo-electric measuring
in vivo-in vitro studies are therefore of great device, changes in vein diameter in response to
interest. locally infused drugs were measured in leg veins
Few methods are available for investigation of dilated by a tourniquet (Steen et al. 1986). T h e
object of the present study was to investigate the
Correspondence : Trygve Sjoberg, Department of effects of noradrenaline, phenylephrine and
Surgery, Lund University, S-22185 Lund, Sweden. clonidine on the human saphenous vein in vivo

463
1u-2
464 T. Sjoberg et al.
and in i'zm. An attempt was made to compare 0.2-mm vertical slit, and a column of light reaches the
the maximum contractile effects a n d relative phototransitor through another 0.2-mm vertical slit in
potencies of the drugs under different experi- the opposite 'foot'. With the device fixed astride a
mental conditions. distended subdermal vein, the phototransistor will be
shaded by the tissue in proportion to the distension of
the vein, i.e. a non-distended or contracted vein will
M A T E R I A I , S A ND M E T H O D S form a smaller shadow than a dilated vein. The signal
from the device, which was linear within the range of
In iiw rxperimenfs measurement, was recorded on a Servogor z (Goerz,
..lustria). T h e measuring device has been used by us in
.rubleits. The investigation was carried out in six a previous study (Steen et al. 1986).
healthy male volunteers aged 23-jj )-ears (mean 33 Exprrimentul conditions. To minimize endogenous
years). .Ill were normotensive non-smokers who were sympathetic tone and achieve a stable venous di-
not on any medication. They had no clinical signs of
latation, the room temperature was maintained at
varicose veins or problems with oedema in the legs. 3-31 "C. The subjects were sitting, placed in a
Equipment .for mrasuremrnt of z'rnous sontrartilit-y. medical treatment chair, Triflex (Bionic GmbH,
The device used to measure changes in venous
FRG), in order to increase venous pressure in the
diameter has a weight of 2 2 g and is made of plastic
lower leg and thereby induce dilatation. An electric
(Fig. I ) . .I photodiode giving infra-red (940 nm) light pad was placed over the abdomen and a blanket over
is placed at the bottom of one 'foot' of the device, and
the total body except the investigated foot, on which
the other 'foot' contains a matched phototransitor.
an electric fan was blowing heated air to maintain a
The light from the photodiode comes out through a skin temperature around 34 "C (Nachev et (11. 1971).
The subjects were asked to relax as much as possible.
Experimental design. T h e measuring device was
fixed astride the long saphenous vein at the medial
malleolus. It was necessary to choose the place for the
device carefully so that the highest (' distended ' vein)
and lowest ('non-distended' vein) altitude of the skin
could be detected by the device. An intravenous
needle (Butterfly-zi) was inserted in an antegrade
direction with the point placed 7-12 mm distal to the
measuring device. T h e needle was connected to a
Gould P23 (Gould Statham Instruments Inc., Puerto
Rico) pressure transducer and the signal was amplified
by and displayed on a Mingograf 4 (Siemens, FRG).
With the subject in the supine position, the leg was
elevated I 5 cm above the manubrium sterni to achieve
a ' non-distended ' vein. A sphygmomanometer cuff
placed just below the knee was inflated via a pressure
reservoir to the occlusion pressure giving an in-
travenous pressure in the foot of 40 mmHg. When the
distension was stable the cuff was deflated. This
procedure was repeated until reproducible responses
Fig. I . The measuring device used to register changes were obtained (3-4 times), and then the cuff was taken
in venous diameter, placed astride a large subdermal away. T h e mean magnitude of the vein diameter
rein. In one 'foot' is a photodiode ( 7 ) giving 940 nm changes caused by repeated inflations and deflations of
infra-red light. The light passes through two 0.2-mm the sphygmomanometer cuff was defined as IOO:~~,
Lcrtical slits and reaches a phototransistor ( c ), placed and used as an internal reference to which subsequent
in the opposite 'foot', measuring variations in light drug-induced contractions were related in each
intensity. Inset: three different levels of the skin. experiment, i.e. ooo when the cuff was inflated
( ' . . . . ' ) indicates ooo contraction (the sphygmo- ('distended' vein), and ~ o o o i ,when the cuff was
manometer cuff was inflated, i.e. 'distended' vein), deflated (' non-distended' vein). Then the position of
( - - ---) indicates
' the level used as 1 0 0 " ~contraction the chair was changed so that the subject came to the
(the cuff' was deflated, i.e. ' non-distended ' vein), and half-sitting position, giving an intravenous pressure of
( ~ - ) ZOO"^, contraction obtained with an intra- 40 mmHg in the foot. T h e pressure transducer was
venous infusion of noradrenaline (concentration in the then disconnected, and the needle was used for the
syringe 3 x I O - ~M). Arrows indicates the light emission infusion of the drugs.
from the photodiode. Cumu1utiz.e dose-rrsponsr curres. An infusion of
Contractility in the human saphenous vein 465
room-temperature 0.904 NaCl (vehicle for the drugs) tractions were related. Noradrenaline, phenylephrine
was given in the foot vein by means of an infusion and clonidine prepared in the same way as the drugs
pump. The piston of the syringe was driven by a used in the in-vivo experiments, and non-sterile
screw, resulting in a stable continuous infusion. All solutions of these drugs with and without cocaine
infusions were done at a rate of 0.3 ml min-'. After I O - ~M and propranolol 3 x 1 0 ~M ' (for control of
15 min the syringe with saline was changed to the influences of neuronal uptake and /j'-adrenoceptors
syringe containing the lowest concentration of drug respectively) were used. It has earlier been found that
( IO..' M). Each concentration was infused for 7 min or higher concentrations of cocaine or propranolol do not
more, and then until no further increase in contraction increase the potency or intrinsic activity of nor-
could be obtained. The next concentration was given adrenaline in human saphenous veins (Steen et a / .
on top of the contraction induced by the preceding 1984a). The agonists were added cumulatively and
concentration. More than 7 days passed between each concentration-response curves were constructed on
experiment in the same subject, and only one drug the basis of the data obtained. E,,,,, and pEC,, values
was used in each experiment. The maximum con- of the different drugs were determined. If Emahwas
traction, Em,,, produced by each agonist was de- less than 10%of the K+-induced contraction (internal
termined. The pEC,, value, i.e. the negative logarithm standard), no pEC,, value was determined (one out of
of the EC,, value, was determined graphically from 18 segments exposed to clonidine). In some cases two
each curve as the concentration giving half-maximal vessel segments from the same patient were exposed
contraction. to the same sterile agonist solution, and then the mean
Heart rate and blood pressure were non-invasively contraction of each concentration was used for
monitored during infusion of each concentration of construction of the concentration-response curve.
the agonists by a Dinamap 845 (Applied Medical Drugs. I n viva and in nitro: clonidine (Catapresan,
Research Corporation, USA) automatic blood pressure Boehringer Ingelheim, FRG) and ( -)-noradrenaline
equipment. (ACO, Sweden) were supplied in ampoules as aqueous
solutions. A stock solution of ( - )-phenylephrine
hydrochloride ( I O - ~ M) (Sigma, USA) was sterile-
In vztro experiments filtered and stored in ampoules at -70 "C until use.
Patients. Eight patients (five women and three men, I n vitro : clonidine hydrochloride (Sigma), cocaine'
aged 37-68 years, mean 47 years) undergoing surgery hydrochloride (Merck, FRG), ( -)-noradrenaline hy-
because of primary varicose veins of the long drochloride, ( - )-phenylephrine hydrochloride and
saphenous system were chosen as vessel donors. All of +
( )-propranolol hydrochloride (Sigma) ; the drugs
them were otherwise healthy and normotensive were dissolved in 0.9% NaCI. I mM ascorbic acid was
without drug treatment of any kind. Half of the added when noradrenaline was used in czvu as well as
operations were performed under epidural anaesthesia, in vitro.
and the other half were carried out under thiopental- Statistics. Wilcoxon signed ranks test for paired
halothane anaesthesia. Earlier experiments have shown data, and Kruskal-Wallis test for unpaired data were
no difference between these two anaesthetic methods used for statistical determinations.
regarding human vein sensitivity to noradrenaline
(Sjoberg et al. 1987).
Preparation, mounttng and experamental procedure. RESULTS
Preparation and mounting of human saphenous veins
in organ baths and the main experimental approach In-vivo experiments
have been described earlier (Steen et al. 1984). The
vessels were repeatedly stretched over 3 h to a steady In the half-sitting position giving a pressure of
basal tension of 7 . 5 k 0 . 8 m ~( n = 60). The distance 40 mmHg in the distal part of the saphenous
between the metal holders at basal tension was vein, the venous distension was stable and the
4.5+o.5mm (n = 36) and the vessel length was infusion of the vehicle did not alter the tone. The
1.2fo.2mm (n = 36) as measured by an operation drugs induced dose-dependent contractions of
microscope, equipped with a scaler. The values are the veins i n all subjects. T h e effects are shown i n
given as mean standard deviation; n is the number Fig. 2 and the Em,, and pEC,, values are given
of preparations.
in T a b l e I . T h e pEC,, values of phenylephrine
The vessels were exposed to a K+-rich (124 mM)
Krebs solution (2-3 times; for composition, see Steen (4.55*0.14) and clonidine (5.39k0.14) were
et al. 1984), until reproducible contractions (variation significantly ( P < 0.05) lower than that of
less than 1o0/) were obtained, an'd the mean amplitude noradrenaline (5.99 0.12). Clonidine had a
of these two (21.5 f 9 . 7 mN; meankstandard de- significantly ( P < 0.05) higher pEC,, value than
viation, 60 preparations) was used as an internal phenylephrine.
standard to which subsequent agonist-induced con- Blood pressure and heart rate did not change
466 T. Sjiiberg et al.

Log Agonist conc (M)


Fig. 2 . Concentration~responsecurves for noradrenaline, phenylephrine and clonidine infused
into the human long saphenous vein. Each point indicates meanfSEM and is expressed as
percentage of the internal reference, i.e. the mean magnitude of the vein diameter changes caused
b> repeated inflations (40 mmHg) and deflations of the sphygmomanometer cuff. n = 6.

significantly from pre-experimental levels during from the investigation. Cocaine I O - ~M and
infusions of phenylephrine or clonidine. T h e propranolol 3 x I O - ~M caused a small but stat-
only significant change was caused by the highest istically non-significant enhancement of the
concentration of noradrenaline ( IO-' M), which contractions induced by concentrations exceed-
increased the mean arterial blood pressure from ing 10-' M of the non-sterile solution of phenyl-
92 j (pre-experimental value) to 102k 7 ephrine. Concentration-response curves for
mmHg (mean SEM; P < 0 . O j ) . sterile solutions of the drugs are shown in Fig. 3.
T h e pEC,, value for sterile solutions of phenyl-
ephrine (5.92 fo.18) was significantly ( P <
In-t'ilro experiments
0.05)lower than for noradrenaline (7.25 +0.12),
A11 vessel segments ( n = 60) showed stable basal whereas there was no statistically significant
tensions, and spontaneous contractions occurred difference between the pEC,, values for sterile
in only one vessel segment, which was excluded solutions of noradrenaline and clonidine (Table
2). Clonidine was significantly (P < 0.05) more
potent than phenylephrine (Table 2).
Table I. In-rive effects of noradrenaline,
phen!-lephrine and clonidine on the distal part of
the human long saphenous vein. The drug-induced Comparison of in-aivo and in-vitro experiments
contractions are expressed as percentage of the vein
expansion caused by a pressure rise from a zero T h e effects in viw and in aitro of phenylephrine
level to an intravenous pressure of 40 mmIIg. and clonidine compared to those of noradrenaline
I ~ a l u e srepresent mean SE.Zl, n = 6 are shown by superpositions of the dose-response
curves obtained in vioo and concentration-
response curves obtained in vitro (Fig. 4). T h e
superpositions were constructed so that the
pEC,, value of noradrenaline in vivo (5.99)lies at
the same point on the abscissa as the pEC,, value
of noradrenaline in citro (7.25).T h i s will mean a
leftward displacement of the in-viao curves of
I .26 (log units). T h e scale of the ordinate for the
Contractility in the human saphenous vein 467

100

Y
L
0

-
s?
c 50
.-
I

-2
c
0

0 1

Log Agonist conc. (M)


Fig. 3. Concentration-response curves for sterile solutions of noradrenaline, phenylephrine and
clonidine in the human long saphenous vein obtained in vitro. Each point indicates mean & SEM
and is expressed as percentage of the K+ (124 mM)-induced contraction. tz = 6.

Table 2. In-vitro effects of noradrenalhe, phenylephrine and clonidine on the distal part of the human
long saphenous vein. The drug-induced contractions are expressed as percentage of the K+ (124 mM)-
induced contraction. Values represent mean & SEM, n = 6

Agonists

Noradrenaline
Sterile solution 106f6 7.25 f0. I 2
Non-sterile solution 106f5 7.40f0.22
Non-sterile solution + 111f6 7.27k0.29
cocaine I O - ~ M and
propranolol3 x 1o-j M

Pheny lephrine
Sterile solution 92f6 5.92k0.18~
Non-sterile solution 89+8 6.01 k0.27
Non-sterile solution + 108i-5 6.06f 0.15
cocaine I O - ~M and
propranolol 3 x 1o-j M

Clonidine
Sterile solution 31 f 8 7.19 fo.13-t n.s.
Non-sterile solution 35f4 6.96 fo.07
Non-sterile solution + 35f5 6.98fo.14
cocaine I O - ~M and
propranolol 3 x 1o-j M

* P < 0.05 compared to sterile solution of noradrenaline.


-f P < 0.05 compared to sterile solution of phenylephrine.
n.s. = not significant compared to sterile solution of noradrenaline.
468 T. Sjoberg et al.

Log Agonist conc. (MI


Fig. 4. Comparative effects of noradrenaline (circles) and phenylephrine (triangles ; upper panel),
and noradrenaline (circles) and clonidine (squares ; lower panel) in ciro (filled symbols) (from Fig.
z) and the concentration-response curves for the same drugs (sterile solutions) in vitro (open
svmbols) (from Fig. 3 ) . T h e superpositions are constructed by leftward displacements by a factor
of I .26 (log units) of the in-rizw curves, giving the same pEC,,, value for noradrenaline in vivo and
rn rrtro. The ordinate scales were made so that the En,axvalues for noradrenaline reached the same
level. Each point indicates mean* SEM and is expressed as percentage of the K+ (124 mM)-
induced contraction (in citro), and percentage of the internal reference (in vivo). n = 6.

zn-z’zzlo contraction was made so that the E,,,, The relative potency (the percentage of the
\slues of both noradrenaline curves reached the pEC,, \ d u e for noradrenaline) of clonidine was
same le\el. As can be seen in Fig. 4, the tn-vtuo significantly lower ( P < 0.05)in vzvo ( 9 0 + 3 ~ / 0 )
and In-urtro curves for phenylephrine were than rn vrtro (99+2yo) (Table 3). There was
~imilar.The clonidine curve obtained rn z w o no statistically significant difference between
appears to lie to the right of the in-city0 curve. relative potencies of phenylephrine zn vzvo
( 7 6 & z o o ) and rn zvtyo (82k2°/0) (Table 3).
Table 3. The relative potencies of phenqlephrine
and clonidine calculated as the percentage of the
pF,Cj,, kalues for noradrenaline in z w o and i n w t r o DISCUSSION
respective11. Values represent mean & SEM, n = 6 In the present study, a photo-electric device
In ZIZO In rrtro described previously (Steen et al. 1986) was
- ~

used. The technique was modified and no


Phen! lephrine 76 k 2 n s . 82 2 O0
tourniquet was used to induce a stable venous
Clonidine 90 f 3 O g x 99k2 dilatation during drug infusions. T h e subjects
* P < 0.05 compared to in ritro. were instead placed in a sitting position creating
n.s. = not significant compared to in u t r o a dilatation of the peripheral veins. B y omitting
Contractility in the human saphenous vein 469
the tourniquet, the blood will pass through the major chemical degradation of the drugs occurred
leg veins in a more physiological way, and leg during the sterilization process. The preser-
swelling which influences the measurements will vatives added to the noradrenaline and clonidine
be minimized. ampoules did not alter the contractile response
The advantage with measuring the local effects to the drugs in vitro. Therefore, the sterile
of drugs is that very low concentrations are agonist solutions were considered appropriate
needed to obtain full dose-response curves for use in vivo.
without affecting blood pressure or heart rate The actual concentration of the drugs in the
significantly. Effects on these variables are often blood is not known, as no continuous blood flow
obtained with other methods used in human measurements were performed. By an elec-
clinical cardiovascular pharmacology (Sumner & tromagnetic blood flow meter (Cliniflow 601D,
Elliott 1987). Carolina Medical Electronics, USA) we have
Zn v i m the contraction-mediating a-adreno- measured the flow in the distal part of the
ceptors in the distal part of the human long saphenous vein in patients before undergoing
saphenous vein have been shown to be mainly of coronary bypass surgery (patients receiving
the a, subtype, although a small population of general anaesthesia ; room temperature kept at
a,-adrenoceptors could not be excluded (Steen about 20 OC; n = 3). It was found that, with the
et al. 1984). It was found that yohimbine patients in the horizontal position, the blood
(selective a,-adrenoceptor blocker) caused a flow varied between 12 and 18rnlmin-', and
concentration-dependent parallel rightward shift when the patients were tilted with the feet down
of the noradrenaline concentration-response the flow varied between 15 and 25 ml min-'.
curve, and the Schild plot gave a PA, value of Under these conditions, blood flow in the
8.27, and a slope that did not differ from I. saphenous vein is most probably lower than in the
Prazosin (selective a,-adrenoceptor blocker), on present investigation. It is reasonable to believe
the other hand, caused no significant shift of the that the blood flow is higher when the room
noradrenaline concentration-response curve. temperature is kept at 3c-31 "C and the skin
The effects of yohimbine and prazosin on temperature of the foot is 34 "C. However, if the
noradrenaline-induced contractions have also data on blood flow are accepted as representative,
been investigated in the same type of vessel in it will mean that with an infusion rate of 0.3 ml
vivo (Steen et al. 1986).In most of the subjects min-' a drug would be diluted 5-80 times if it
participating in that study, prazosin had a more was infused into the vein.
pronounced effect than yohimbine. It was In the present study, the noradrenaline
suggested that both a,- and a,-adrenoceptors dose-response curve obtained in vivo had to be
are of functional significance for mediating displaced to the left by a factor of 1.26 to be
responses to noradrenaline in the human sa- superimposable on the noradrenaline concentra-
phenous vein in vivo. T o our knowledge selective tion-response curve obtained in vitro. If the only
a-adrenoceptor agonists have not previously reason for the displacement was a dilution of the
been used to characterize a-adrenoceptors in the drug when it was infused into the vein,
human saphenous vein in vivo. noradrenaline would be diluted 18 times (the
Phenylephrine and clonidine are considered to antilogarithm of I .26).If the blood flow recorded
have a preference for a,- and a,-adrenoceptors in the patients undergoing heart surgery was
respectively (Timmermans & van Zwieten 1982, valid also in the present study, this indicates that
Ruffolo 1984), even though the selectivity of noradrenaline was at least three times more
clonidine for a,-adrenoceptors has been ques- potent in vivo than in vitro. However, other
tioned (Timmermans et al. 1980). However, it factors may also play a role in the magnitude of
was shown that clonidine was more potent on displacement of the noradrenaline curves ; the
human saphenous (Steen et al. 1984) and blood contains several other substances (e.g.
epigastric veins (Sjoberg et al. 1987) than other hormones, prostanoids, peptides) which
naphazoline, guanfacine, B-HT 920 and B-HT may interfere with the action of noradrenaline
933, other agonists with preferential effects on and the other drugs. Differences in the ex-
a,-adrenoceptors, perimental approaches may also affect the
The similar effects of sterile and non-sterile magnitude of displacement of the noradrenaline
agonist solutions in the baths indicate that no curves.
19 A C T 136
470 T. Sjoberg et al.
T h e relative potencies given in Table 3 show may exist between in-vivo and in-vitro effects of
that, compared to noradrenaline, phenylephrine some a-adrenoceptor-selective agonists. This is
was almost as potent in zico as in ritro. Clonidine, in accordance with previous findings obtained
on the other hand, had a significantlq- lower (P< with a-adrenoceptor-selective antagonists (Steen
0.05)potency in zico than in citro. This may et al. 1986). Therefore, comparative in vivo-
have different explanations. One reason may be i n ritro studies are of great clinical relevance.
interference of blood-borne factors (e.g. binding
to platelets), causing an apparently decreased
potency of clonidine. Another reason may be
that in the in-cico situation the endothelium is
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