Full text of DOI:10.1038/sj.bjp.0704670

British Journal of Pharmacology (2002) 136, 90 ± 94
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Relaxation by urocortin of human saphenous veins
1
1
1
2
1Elena Sanz, Luis Monge, Nuria Fernandez, Marõa Angeles Martõnez, Juan B. Martõnez-Leon,
1Godofredo Dieguez & *,1Angel Luis Garcõa-Villalon
2
1Departamento de Fisiologõa, Facultad de Medicina, Universidad Autonoma, 28029 Madrid, Spain and Departamento de
Cirugõa, Universidad de Valencia, Spain
1
Urocortin, an endogenous peptide structurally related to corticotropin-releasing factor (CRF),
has potent cardiovascular e€ects, suggesting that it may be of signi®cance in cardiovascular
regulation. The objective of this study was to analyse the e€ects of urocortin and its action
mechanisms on human blood vessels.
2
To this, 3 mm long segments from human saphenous veins were prepared for isometric tension
recording in an organ bath.
In the segments at basal resting tone, urocortin did not produce any e€ect, but in the segments
3
precontracted with endothelin-1 (1 ± 10 nM), urocortin (1 pM ± 10 nM) produced concentration-
dependent relaxation.
4
This relaxation was not modi®ed by the inhibitor of nitric oxide synthase NG-nitro-L-arginine
methyl ester (L-NAME, 100 mM), but it was potentiated by the cyclo-oxygenase inhibitor
meclofenamate (10 mM) and it was reduced by the inhibitors of high-conductance Ca2+-dependent
potassium channels tetraethylammonium (TEA, 10 mM) and charybdotoxin (100 nM).
5
These results indicate that human saphenous veins are very sensitive to urocortin, which
produces vascular relaxation by a mechanism independent of nitric oxide and dependent of high-
conductance Ca2+-dependent potassium channels, and that it may be opposed by the release of
vasoconstrictor prostanoids. Therefore, urocortin may be of signi®cance for regulation of the venous
circulation in humans.
British Journal of Pharmacology (2002) 136, 90 ± 94
Keywords: Ion channels; peptides; prostaglandins; vasodilation; veins
Abbreviations: CRF, corticotropin-releasing factor; L-NAME, NG-nitro-L-arginine methyl ester; TEA, tetraethylammonium
Introduction
Urocortin is a recently isolated 40 amino acid peptide, which
has a high degree of structural homology with corticotropin-
releasing factor (CRF), and belongs to a group of structurally
related peptides which includes, in addition to urocortin and
CRF, ®sh urotensin I and amphibian sauvagine (Parkes &
May, 2000).
binds to cardiovascular receptors and mediates their
cardiocirculatory e€ects (Parkes et al., 2001). In rats,
intravenous urocortin produce potent and long lasting
hypotension which might be due to systemic vasodilation,
and tachycardia, probably in part barore¯ex mediated
(Vaughan et al., 1995). Indeed, it has been shown that this
peptide produces relaxation of rat basilar arteries (Schilling et
al., 1998) and of rat coronary circulation (Terui et al., 2001).
In mice, urocotin also produces hypotension, which is
abolished in knockout mice with the CRF ± R2 receptor
subtype inactivated (Bale et al., 2000; Coste et al., 2000).
Interestingly, these knockout mice have elevated resting
blood pressure, suggesting that activation of CRF ± R2
receptors may play a role in regulation of basal vascular
tone (Coste et al., 2000). However, there may exist species
di€erences in the vascular e€ects of urocortin, as in sheep this
peptide increases systemic blood pressure, in addition to
increasing cardiac contractility (Parkes et al., 1997).
CRF and urocortin may act as neurotransmitters in the
central nervous system and may also act on peripheral
tissues, particularly in the cardiovascular system. These
peptides produce potent e€ects on the cardiovascular system
when administered both intravenously or directly into the
central nervous system (Parkes & May, 2000; Parkes et al.,
2001). It has been observed that the e€ects of intravenous
urocortin are more potent than those of CRF, probably
because the anity of urocortin is higher than that of CRF
for the subtype of CRF ± R2b receptors (Vaughan et al.,
1995), which are expressed in peripheral tissues (Perrin et al.,
1995). Moreover, urocortin mRNA is expressed in smooth
muscle cells of blood vessels and in cardiac myocites (Parkes
& May, 2000). Because of that, it has been suggested that
urocortin may be the endogenous CRF-like peptide that
All these observations have aroused the interest for the
possible role of urocortin in cardiovascular regulation. In
addition, urocortin is produced in human hearts, and it
increases in failing hearts (Nishikimi et al., 2000), suggesting
that this peptide could be involved in human cardiovascular
regulation under normal and pathologic conditions. Con-
sidering that there is marked species variability in the
*Author for correspondence: Departamento de Fisiologõa, Facultad
de Medicina, Universidad Autonoma, arzobispo Morcillo 2, 28029
Madrid, Spain; E-mail: angeluis.villalon@uam.es

E. Sanz et al
Urocortin and human blood vessels
91
cardiovascular e€ects of urocortin, these e€ects should be
also studied in human tissues before the results obtained in
animals can be extrapolated to humans. To our knowledge,
there is only one study analysing the response to urocortin in
human blood vessels, this study shows that this peptide
produces dilatation of human perfused placenta (Leitch et al.,
1998). Therefore, the objective of our study was to analyse
the e€ects of urocortin on human blood vessels, using
segments from human saphenous veins. The role of nitric
oxide, prostanoids and potassium channels in the vascular
e€ects of urocortin were also examined.
relaxation which was 16+7% of the remaining tone. This is
the typical response to acetylcholine of intact human
saphenous arteries (Sogo et al., 2000).
The relaxation to urocortin in the precontracted segments
was studied in segments pretreated with the inhibitor of nitric
oxide synthesis NG-nitro-L-arginine methyl ester (L-NAME,
100 mM), with the cyclo-oxygenase inhibitor meclofenamate
(10 mM), and with the inhibitors of high-conductance Ca2+
-
dependent potassium channels tetraethylammonium (TEA,
1 ± 10 mM) or charybdotoxin (100 nM), to analyse the role of
nitric oxide, prostanoids and potassium channels in this
relaxation to urocortin. These blockers were added to the
organ bath 20 min before beginning the concentration
response curve to urocortin. As the segments pretreated with
Methods
TEA developed
a greater level of active tone when
For this study, saphenous veins from 12 patients (nine males
and three females), aged between 45 and 83 years, were used.
The veins were obtained during coronary bypass artery
surgery and placed in ice isotonic cold saline solution for
transportation to the laboratory. Under a dissecting micro-
scope, they were cleaned from surrounding tissue, cut in
segments 3 mm long and prepared for isometric tension
recording in a 4 ml organ bath, containing modi®ed Krebs ±
Henseleit solution with the following composition (milli-
molar): NaCl, 115; KCl, 4.6; KH2PO4, 1.2; MgSO4, 1.2;
CaCl2, 2.5; NaHCO3, 25; glucose, 11. The solution was
equilibrated with 95% oxygen and 5% carbon dioxide to give
a pH of 7.3 ± 7.4, and maintained at 378C. Brie¯y, the method
consists of passing through the lumen of the vascular segment
two stainless steel wires, 150 mm in diameter. One wire is
®xed to the organ bath wall, while the other is connected to a
strain gauge for isometric tension recording, thus permitting
the application of passive tension in a plane perpendicular to
the long axis of the vascular cylinder. The recording system
precontracted with endothelin-1 (1 ± 10 nM), a group of
control segments were precontracted with a higher concen-
tration of endothelin-1 (10 ± 30 nM) to reach a level of tone
similar to that in the segments pretreated with TEA plus
endothelin-1, in order to test whether this elevated tone may
a€ect by itself the relaxation to urocortin
The relaxation to urocortin is expressed as percentage of
the active tone reached, and calculated as means+s.e.mean.
The results were analysed by one-way ANOVA, followed by
Dunnet's test to compare each experimental condition with
control. P50.05 was considered as signi®cant.
The substances used were: charybdotoxin; meclofenamic
acid (2-[(2,6-Dichloro-3-methyl-phenyl)amino]benzoic acid)
sodium salt; L-NAME; tetraetylammonium chloride; and
urocortin human; all from Sigma; and endothelin-1 (human,
porcine) from Peninsula Laboratories Europe, Ltd.
Results
included
Instruments, Inc.), a Statham Microscale Accessory UL5
(Statham Instruments, Inc.) and Beckman Type RS
a Universal Transducing Cell UC3 (Statham
In the vein segments at basal, resting tension, urocortin (1 pM ±
10 nM) did not produce any e€ect (six segments from three
individuals) (Figure 1). In the vein segments precontracted with
endothelin-1 (1 ± 10 nM, mean active tone=8.5+0.75 mN),
urocortin produced concentration-dependent relaxation (Fig-
ures 1 and 2). This relaxation was not signi®cantly modi®ed by
pretreatment with L-NAME (100 mM), but it was potentiated
(P50.01) by the cyclo-oxygenase inhibitor meclofenamate
a
Recorder (model R-411, Beckman Instruments, Inc.). To
establish the resting tension for maximal force development,
a series of preliminary experiments was performed on vein
rings of similar length and outer diameter that were exposed
repeatedly to KCl 100 mM. Basal tension was increased
gradually until contractions were maximal, and the optimal
resting tension was 30 mN. This tension was applied to all
the vascular segments. When the veins were stretched
immediately after placed in the bath, they often developed
spontaneous myogenic tone. To avoid this, in the present
experiments, the vascular segments were kept in the bath at
zero tension for 30 min before being stretched to the passive
tension of 30 mN. In these conditions, they did not develop
any apparent spontaneous contraction over the resting
tension, and were equilibrated for 60 ± 90 min at this basal
passive tension until they were stimulated.
The responses to cumulative concentrations of human
urocortin (1 pM ± 10 nM) were recorded in the segments of
saphenous veins at basal, resting tension after applying the
optimal passive tension, and also in vein segments precon-
tracted with endothelin-1 (1 ± 10 nM). To asses the functional
status of the endothelium, acetylcholine 10 mM was added
cumulatively to the bath in the arteries precontracted with
endothelin-1, after recording the e€ects of the last urocortin
concentration. In this case, acetylcholine produced a further
(10 mM) (Figure 2). The antagonist of high conductance, Ca2+
-
sensitive potassium channels charybdotoxin (100 nM) reduced
(P50.05) the relaxation to urocortin. Also, TEA, which is an
antagonist of this same type of potassium channels, reduced the
relaxation to urocortin at a concentration of 10 mM (P50.05)
but not at 1 mM (Figure 2).
The active tone developed by precontraction with
endothelin-1 (1 ± 10 nM) tended to be higher in the segments
pretreated with L-NAME (10.9+2.2 mN), meclofenamate
(15.6+3.2), charybdotoxin (16.1+2.7 mN) or TEA (1 mM,
19.9+2.5 mN; 10 mM, 25+3.7 mN) than in control seg-
ments, although this increase was statistically signi®cant
(P50.01) only in those treated with 10 mM TEA. To test
whether this elevated tone could a€ect the relaxation to
urocortin, a group of control segments (®ve segments from
®ve individuals) were precontracted with a higher concentra-
tion of endothelin-1 (10 ± 30 nM) to reach a level of tone
(19.3+1.2 mN) which was not signi®cantly di€erent from
that in the segments treated with TEA plus endothelin-1. In
British Journal of Pharmacology vol 136 (1)

92
E. Sanz et al
Urocortin and human blood vessels
Figure 1 Actual recordings of the e€ects of urocortin (1 pM ±
10 nM) on one segment of human saphenous vein at basal, resting
tone (top), and on another segment of saphenous vein precontracted
with endothelin-1 (5 nM) (bottom).
Figure 2 Summary of the relaxation to urocortin (1 pM ± 10 nM) of
human saphenous veins precontracted with endothelin-1 (1 ± 10 nM)
in the absence (control, 15 segments from 12 individuals) and in the
presence of L-NAME (100 mM, 14 segments from 12 individuals),
meclofenamate (10 mM, 14 segments from 12 individuals), charybdo-
toxin (100 nM, 20 segments from 12 individuals), or TEA (10 mM,
seven segments from ®ve individuals). Statistically signi®cant
compared to control (*P50.05; **P50.01).
those control segments precontracted with a higher concen-
tration of endothelin-1 and showing a higher level of tone
(19.3+1.2 mN), the relaxation to urocortin was similar to
that in the control segments precontracted with a lower
concentration of endothelin-1 and showing a lower level of
tone (8.5+0.75 mN) (data not shown).
nitric oxide by the vascular wall, as it was not modi®ed by
the nitric oxide synthase inhibitor L-NAME, and the
concentration of this inhibitor we have used (100 mM) may
be enough to markedly reduce nitric oxide synthesis
(Fernandez et al., 1994). This lack of nitric oxide participa-
tion agrees with that observed in the coronary circulation of
rat, in which the relaxation to urocortin was not inhibited by
nitric oxide inhibition (Terui et al., 2001). In the basilar
artery of rat, the e€ect of urocortin is not modi®ed by
endothelium removal, suggesting that this peptide acts
directly on the smooth muscle of the vascular wall (Schilling
et al., 1998). Contrarily, the relaxation to CRF in the rat
coronary circulation is partly dependent on nitric oxide
(Grunt et al., 1993). Thus, there may be di€erences between
these two peptides in their mechanisms of vascular action.
We have also observed that the relaxation to urocortin was
reduced by TEA and by charybdotoxin, which are both
blockers of potassium channels of the high-conductance
Ca2+-sensitive subtype. Although the vessel segments pre-
treated with these blockers developed a higher active tone
when precontracted with endothelin-1, this higher tone
probably is not the cause of the reduced relaxation to
urocortin, because induction of a higher tone with a higher
concentration of endothelin-1 did not modify the relaxation
to urocortin. In the rat isolated basilar artery also it has been
observed that the relaxation to urocortin is reduced by
antagonists of high-conductance Ca2+-sensitive potassium
channels, such as TEA or iberiotoxin (Schilling et al.,
1998), as occurred in our experiments. Therefore, it may be
suggested that urocortin produces vascular relaxation by
activating potassium channels in smooth muscle cells.
Discussion
The present study was performed in vitro using 3 mm long
segments of human saphenous veins under isometric conditions,
and the results show that urocortin produces concentration-
dependent relaxations of these veins, and this relaxation was
evident with very low (1 pM) concentrations of this peptide.
Therefore, human saphenous veins are very sensitive to
urocortin, and although our in vitro results can not be directly
extrapolated to in vivo function, we may suggest that the
magnitude of the observed vein relaxation might represent
relatively great changes of vessel wall tension, and thus great
displacements of blood volume in the in vivo venous circulation.
Urocortin concentrations of 1 pM correspond to the plasma
levels measured in humans (Watanabe et al., 1999), and, as
urocortin can be produced by systemic tissues such as the heart
(Nishikimi et al., 2000), our results suggest that urocortin may be
relevant to the regulation of the venous circulation in humans.
Our results in human veins compare with those obtained in rat
isolated basilar artery by Schilling et al. (1998) and in human
perfused placenta by Leitch et al. (1998), who found that
urocortin relaxed these vascular beds at very low concentrations
(1 ± 10 pM). These two studies also report that the sensitivity of
these vascular beds for urocortin was higher than that for CRF,
suggesting that urocortin may be the physiological endogenous
activator of cardiovascular CRF receptors. Urocortin also may
dilate cat cerebral (Yatsushiro et al., 1997) and sheep coronary
(Parkes et al., 1997) arteries in vivo.
Regarding the mechanisms of the vasodilation by urocor-
tin, our results suggest that this e€ect is not due to release of
British Journal of Pharmacology vol 136 (1)

E. Sanz et al
Urocortin and human blood vessels
93
Potassium channels seem to mediate the vascular relaxation
to several substances (adenosine, prostacyclin or epoxides of
arachidonic acid) which act directly on vascular smooth
muscle. Opening of potassium channels produces hyperpolar-
ization of smooth muscle membrane, and subsequent
relaxation of smooth muscle cell (Jackson, 2000).
urocortin increases the release from human trophoblast tissue
of the vasodilator prostaglandin E2, but also urocortin
potentiates the contracting e€ects of prostaglandin F2a on
human myometrium (Petraglia et al., 1999). It may be
hypothesized that urocortin may increase the release and/or
the e€ects of both contracting and dilating prostanoids, and
that either of these may predominate depending on the type
of blood vessel (arterial or venous), and perhaps of vascular
bed or species.
Since the relatively recent discovery of urocortin, evidence
has been found suggesting that this peptide may have
signi®cant cardiovascular functions, not only under normal
conditions, but also under pathological conditions such as
cardiac ischemia (Brar et al., 2000) and cardiac failure
(Nishikimi et al., 2000). Our present results, showing that
urocortin produces marked dilation at very low concentra-
tions in human veins, suggest that this peptide should be
considered as a factor involved in the physiology and/or
pathophysiology of the venous circulation in human beings.
Regarding the role of prostanoids, our results suggest that
the vasodilation to urocortin may be modulated by the
release of cyclo-oxygenase products. This vasodilation was
potentiated by the cyclo-oxygenase inhibitor meclofenamate,
thus suggesting that vasoconstricting prostanoids may be
released from the vascular wall of urocortin-stimulated
human saphenous veins, and this release may oppose the
dilating e€ect of urocortin. It has been reported that the
relaxation to acetylcholine in human saphenous veins may
also be increased by cyclo-oxygenase inhibition (Yang et al.,
1991). Consequently, it may be hypothesized that vasocon-
strictor prostanoids released by the venous wall may
modulate the response to di€erent vasodilator stimuli,
including urocortin. Indeed, the venous endothelium may
have a higher capacity to release vasoconstrictor factors than
the arterial endothelium (Garcõa-Villalon et al., 1993). Our
results contrast, however, with those of Terui et al. (2001),
who have reported that the in vitro relaxation of rat coronary
circulation to urocortin was reduced by cyclo-oxygenase
inhibition, and suggested that this relaxation may be
mediated by the release of vasodilating prostaglandins. The
interaction of urocortin with prostanoids may be complex, as
We are indebted to Hortensia Fernandez-Lomana and Marõa Ester
Martõnez by technical assistance. This study was supported by
MEyC (SAF 1999-0004), FIS 899/0224) and CAM (08-4/0003/
1998).
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(Received September 21, 2001
Revised December 27, 2001
Accepted February 11, 2002)
British Journal of Pharmacology vol 136 (1)