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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
JPET 286:1315–1320, 1998
Vol. 286, No. 3
Printed in U.S.A.
Role of Vasopressin on Adrenergic Neurotransmission in
Human Penile Blood Vessels1
GLORIA SEGARRA, PASCUAL MEDINA, CRISTINA DOMENECH, JOSÉ M. VILA, JUAN B. MARTÍNEZ-LEÓN,
MARTÍN ALDASORO and SALVADOR LLUCH
From the Departments of Physiology (G.S., P.M., J.M.V., M.A., S.L.) and Surgery (C.D., J.B.M.-L.), University of Valencia, 46010, Valencia,
Spain
Accepted for publication May 5, 1998
This paper is available online at http://www.jpet.org
Vasopressin (AVP) causes powerful constriction in a variety of vascular regions through V1 receptor activation and
promotes reabsortion of water in renal tubular cells through
V2 receptors coupled to adenylate cyclase activation (Michell
et al., 1979; Penit et al., 1983). With regard to human vessels,
vasopressin causes powerful V1 receptor mediated constriction in isolated mesenteric, (Martı́nez et al., 1994b; Ohlstein
and Berkowitz, 1986) cerebral (Lluch et al., 1984; White and
Robertson, 1987) and renal (Medina et al., 1996) arteries.
Vasopressin may also modify the effects of other vasoactive
substances that are found in plasma or released from
perivascular nerve endings (Bartelstone and Nasmyth, 1965;
Karmazyn et al., 1978; Guc et al., 1992). In the human forearm AVP attenuates phenylephrine-induced vasoconstriction
(Harada et al., 1991) whereas recent experiments in human
isolated mesenteric arteries show that AVP enhances adrenergic mediated responses (Medina et al., 1997).
The presence of high concentrations of vasopressin in human testis (Nicholson et al., 1984), and in penile erectile
tissue (Andersson et al., 1987) together with the pharmacoReceived for publication March 6, 1998.
1
This work was supported by the Comisión Interministerial de Ciencia y
Tecnologı́a, Ministerio de Sanidad and Generalitat Valenciana.
contrast, the V2 receptor antagonist [d(CH2)5,D-Ile2, Ile4,Arg8]vasopressin (1028-1027 M) did not prevent the potentiation
induced by vasopressin. The results demonstrate that vasopressin exerts powerful constrictor action in human penile arteries and veins by direct stimulation of V1 receptors. In addition, vasopressin strongly potentiates the contractions to
norepinephrine and stimulation of perivascular adrenergic
nerves. Consequently, the direct contractile effects of vasopressin together with its amplifying effects on adrenergic-mediated constriction should be taken into consideration in the
overall regulation of penile erection and in those states characterized by increased plasma vasopressin levels.
logical characterization of specific V1 receptors in this tissue
(Andersson et al., 1988; Maggi et al., 1989) suggest that the
hormone is taken up and/or synthetized locally (Andersson et
al., 1987). Vasopressin was found to contract isolated human
corpus cavernosum and spongiosum and preparations of the
cavernosal and deferential artery (Hedlund and Andersson,
1985; Andersson et al., 1987; Medina et al., 1996). At present
there is no information concerning the effects and pharmacological receptors of vasopressin in human penile dorsal
arteries and veins. Furthermore, the possibility exists that
AVP could importantly affect neurogenic vascular tone if this
peptide would facilitate sympathetic neurotransmission or
sensitize the smooth muscle to the effects of norepinephrine.
This might have important implications in understanding
the increase in penile smooth muscle tone resulting from
excessive sympathetic outflow or increased blood catecholamine levels (von Euler, 1964; Diederichs et al., 1991). An
increase in smooth muscle tone would oppose the relaxation
necessary for erection. Therefore we designed this study to
examine the direct effects of vasopressin on isolated human
penile dorsal artery and deep dorsal vein. The second aim of
the present study was to establish whether low concentrations of vasopressin could modify the constrictor responses of
ABBREVIATIONS: AVP, arginine-vasopressin; d(CH2)5Tyr(Me)AVP, [(1-(b-mercapto-b,b-cyclopentamethylenepropionic acid)-2-(O-methyl)-tyrosine, 8-arginine) vasopressin]; desmopressin, deamino-8-D-arginine vasopressin.
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ABSTRACT
We have used in vitro preparations of human penile dorsal
artery and deep dorsal vein from 20 multiorgan donors to
investigate whether subpressor concentrations of vasopressin
facilitate noradrenergic transmission in penile blood vessels.
Vasopressin constricted penile dorsal arteries (pD2, 9.38 6
0.18) and deep dorsal veins (pD2, 9.40 6 0.14) by activating V1
receptors. Vasopressin (10211 and 3 3 10211 M) caused concentration-dependent potentiation of the contractions elicited
by electrical stimulation (15 V, 0.5–2 Hz, 0.2 msec duration for
15 sec) and produced leftward shifts of the concentrationresponse curve for norepinephrine. The V1 receptor antagonist
d(CH2)5Tyr(Me)AVP (3 3 1029-1027 M) induced concentrationdependent inhibitions of potentiation caused by vasopressin. In
1316
Segarra et al.
Vol. 286
these vessels to adrenergic stimulation, analyzing the receptor subtypes involved.
Methods
Results
Effects of vasopressin. Vasopressin (10211-1027 M)
caused concentration-dependent contractions in arteries and
veins (fig. 1). The maximal contractions to vasopressin and
pD2 values are shown in table 1. The presence of the V1
receptor antagonist d(CH2)5Tyr(Me)AVP (1028-1026 M) induced significant shifts (P , .05) of the control curve to the
right in a concentration-dependent manner, but differences
in the maximal tensions developed were not significant (fig.
1). The a1 adrenoceptor blocker prazosin (1026 M) did not
affect the concentration response curves to vasopressin (fig.
1). The pA2 and slope values obtained for the V1 antagonist in
arteries and veins are shown in table 1.
The selective antidiuretic agonist desmopressin (102111027 M) did not produce changes in the resting tension of
arteries and veins (n 5 4). In addition, the presence of desmopressin (1027 M) did not affect the contractile responses to
vasopressin (n 5 4, results not shown).
Responses to 100 mM KCl were 3045 6 146 mg in artery
segments (n 5 10), and 4079 6 177 mg in vein segments (n 5
10).
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Penile dorsal arteries and deep dorsal veins were obtained from 20
multiorgan donors during procurement of organs for transplantation
(age range: 17–71 years). The study was approved by the ethical
committee of our institution. The vessels were immediately placed in
chilled Krebs-Henseleit solution, and rings 3 mm long were cut
under a dissecting microscope (Heerbrugg, Switzerland) for isometric recording of tension.
Two stainless steel L-shaped pins 100 mm in diameter were introduced through the lumen of the ring. One pin was fixed to the wall of
the organ bath, while the other was connected to a force-displacement transducer (Grass FT03). Changes in isometric force were
recorded on a Grass polygraph (model 7). Each ring was set up in a
4 ml bath containing modified Krebs-Henseleit solution of the following millimolar composition: NaCl, 115; KCl, 4.6; MgCl2.6H2O,
1.2; CaCl2, 2.5; NaHCO3, 25; glucose, 11.1 and disodium EDTA, 0.01.
The solution was equilibrated with 95% O2 and 5% CO2 to give a pH
of 7.3–7.4. Temperature was held at 37°C. To establish the resting
tension for maximal force development, a series of preliminary experiments were performed on rings of similar length and outer
diameter which were exposed repeatedly to 100 mM KCl. Basal
tension was increased gradually until contractions were maximal.
The optimal resting tension was 3.5 g for the artery and 3 g for the
vein. The rings were allowed to attain a steady level of tension
during a 2–3 hr accommodation period before testing. Functional
integrity of the endothelium was confirmed routinely by the presence
of relaxation induced by acetylcholine (1027-1026 M) or substance P
(1029-1028 M) during contraction obtained with norepinephrine
(1027-3 3 1027 M).
Following the equilibration period, concentration-response
curves for vasopressin (10211-1027 M) were obtained in paired
rings in the absence and in the presence of the V1 antagonist
d(CH2)5Tyr(Me)AVP (1028-1026 M).
Electrical field stimulation was provided by a Grass S88 stimulator (Grass Instruments, Quincy, MA) via two platinum electrodes
positioned on each side and parallel to the axis of the vessel ring. To
assess the nature of the contractile responses and avoid direct stimulation of smooth muscle, frequency-response relationships were
determined on a group of vessels in the presence and absence of 1026
M tetrodotoxin, following procedures previously described (Martı́nez
et al., 1995, 1994a; Aldasoro et al., 1993). In summary, the protocol
was designed to find the optimal stimulation parameters causing a
contractile response that was completely eliminated by 1026 M tetrodotoxin. Stimulation was conducted at 15 V for 15 sec at frequencies of 0.5, 1 and 2 Hz. A pulse width of 0.2 msec was used. A period
of 10 –15 min was allowed between stimulations.
To study the effects of vasopressin and the V2 agonist desmopressin on electrical field stimulation-induced responses, frequency-response relationships were determined in a separate group of experiments. After an initial set of stimulations, the vessel rings were
consecutively incubated with increasing concentrations of vasopressin (10212-3 3 10211 M) or desmopressin (10210-1028 M) for 10 min
before another set of stimulations was given. As a control, four
consecutive sets of stimulations were given to a group of untreated
rings at identical intervals. Less than 10% variability in magnitudes
of electrical field stimulation-induced contractions was observed for
a given ring during four consecutive sets of control stimulations.
In another series of experiments, the rings were incubated with
the V1 receptor antagonist d(CH2)5Tyr(Me)AVP (3 3 1029-1027 M) or
the V2 receptor antagonist [d(CH2)5,D-Ile2,Ile4,Arg8]-vasopressin
(1028-1027 M) for 10 min and then exposed to vasopressin (10211 M).
Electrical field stimulation was obtained in these rings and the data
compared with rings in the absence of antagonists.
To determine whether vasopressin could block the reuptake of
norepinephrine and therefore enhance the neurogenic induced contractions, the reuptake blocker cocaine (1026 M) was used in some
experiments 10 min before the addition of vasopressin.
Concentration-response curves for norepinephrine were determined in a cumulative manner. Control (in the absence of vasopressin) and experimental (in the presence of vasopressin) data were
obtained from separate vascular preparations. Another group of
rings were incubated with the V1 antagonist (3 3 1028 M) before
exposure to vasopressin and norepinephrine.
Drugs. The following drugs were used: tetrodotoxin, guanethidine, prazosin hydrochloride, norepinephrine hydrochloride, acetylcholine chloride, substance P, arginine vasopressin acetate salt, [(1(b-mercapto-b,b-cyclopentamethylenepropionic acid)-2-(O-methyl)tyrosine, 8-arginine) vasopressin] (d(CH2)5Tyr(Me)AVP), deamino-8D-arginine vasopressin (desmopressin), (Sigma Chemical Co, St.
Louis, MO, U.S.A.), [d(CH2)5, D-Ile2,Ile4,Arg8]-vasopressin (Peninsula Laboratories Europe, Merseyside, England) and cocaine chlorhydrate (Abelló, Madrid, Spain). All drugs were dissolved in Krebs
solution. Drugs were added to the organ bath in volumes of less than
70 ml. Stock solutions of the drugs were freshly prepared every day,
and kept on ice throughout the experiment.
Data analysis. All values are expressed as mean 6 S.E. Contractions are reported as a percentage of response to KCl (100 mM). pD2
(negative logarithm of the molar concentration at which half-maximum contraction occurs) was determined from individual concentration-response curves by nonlinear regression analysis. The pA2 values for V1 vasopressin receptor antagonist were determined from a
Schild plot (Arunlakshana and Schild, 1959). The concentration ratios (CR) were calculated as the ratio between the EC50 value (concentrations producing half-maximal contractions) for vasopressin in
the presence and absence of different concentrations of the antagonist. A Schild plot was constructed with the CRs: log (CR-1) (ordinate
scale) was plotted against log (antagonist concentration) (abscissa
scale) and pA2 was estimated as the intercept of the regression line
with the abscissa scale (Arunlakshana and Schild, 1959). Concentration-response curves of the tested agonists or frequency-response
relationships were performed in rings obtained from the same patient; the responses obtained in each patient were averaged to yield
a single value. Therefore, all n values are presented as the number of
individuals from whom the rings were obtained. For electrical stimulation experiments, in which the same rings were stimulated in the
absence and presence of antagonists, a paired t test was used. Statistically significance was accepted at P , .05.
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Vasopressin and Human Penile Blood Vessels
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Fig. 1. Concentration-response curves for vasopressin in
dorsal arteries and deep dorsal veins in the absence (F),
and in the presence of V1 antagonist d(CH2)5Tyr(Me)AVP
(E, 1028 M; f, 1027 M; M, 1026 M) or in the presence of
the a1 adrenergic antagonist prazosin (‚, 1026 M).
Vasopressin
Maximal
contraction
V1 antagonist
pD2
pA2
Slope
9.38 6 0.18
9.40 6 0.14
8.98 6 0.08
8.96 6 0.05
0.97 6 0.07
1.05 6 0.04
%
Artery (n 5 6)
Vein (n 5 6)
141 6 9
110 6 4
Values are mean 6 S.E. Maximal contraction is expressed as a percentage of
response to 100 mM KCl.
n, number of patients.
Effects of vasopressin on electrical stimulation -induced responses. Electrical stimulation induced frequencydependent increases in tension in both arteries and veins
which were abolished by tetrodotoxin, guanethidine and prazosin (all at 1026 M), thus indicating that the effect was due
to the release of norepinephrine from adrenergic nerve endings acting on alpha-1 adrenoceptors.
Vasopressin 10212 M did not cause any contractions nor
did it enhance the contractions to electrical stimulation. Vasopressin 10211 M did not induce contractions but significantly augmented the neurogenic-mediated contractions in
arteries and veins. At 3 3 10211 M, vasopressin further
potentiated the neurogenic contractions (fig. 2).
The presence of the V 1 receptor antagonist
d(CH2)5Tyr(Me)AVP (3 3 1029-1027 M) did not change control responses to electrical stimulation but prevented the
amplifying effect of vasopressin in a concentration-dependent manner (fig. 3). At a concentration of 3 3 1028 M, the V1
antagonist abolished the potentiation induced by 10211 M
vasopressin. Higher concentrations of the V1 antagonist
(1027 M) did not produce further inhibition (fig. 3). Both the
potentiating effects of vasopressin and the inhibition of this
potentiation occurred at all the frequencies used (fig. 4).
To determine whether V2 receptors are involved in the
effects of vasopressin on electrical field stimulation, frequency-response relationships were obtained in the absence and
in the presence of the V2 receptor agonist desmopressin.
Figure 5 shows that increasing concentrations of desmopressin (10210-1028 M) did not change neurogenic-induced contractions. On the other hand, the potentiation induced by
Fig. 2. Top. Original tracings of contractile responses to electrical field
stimulation (1 Hz) of human penile dorsal artery and deep dorsal vein
under control conditions and after incubation with various concentrations
of vasopressin (10212 to 3 3 10211 M). Bottom. Bar graphs of contractile
responses to electrical stimulation (1 Hz) in the absence and in the
presence of vasopressin. * P , .05 vs. control.
vasopressin (10211 M) was not modified in the presence of the
V2 receptor antagonist [d(CH2)5,D-Ile2,Ile4, Arg8]vasopressin
(1028-1027 M) (P . .05, n 5 4; results not shown).
Blockade of neuronal catecholamine reuptake by cocaine
(1026 M) had no effect on the potentiating effects of vasopressin on neurogenic contractions (fig. 6).
Effects of vasopressin on norepinephrine induced
contraction. Norepinephrine induced concentration dependent contraction in penile arteries and veins (fig. 7). In the
presence of vasopressin (3 3 10211 M) the concentration
response curves to norepinephrine were displaced to the left
without changing maximal contractions. The V1 receptor antagonist (3 3 1028 M) completely reversed the vasopressininduced potentiation (fig. 7 and table 2).
Discussion
Our experiments provide the first evidence for the powerful constrictor action of vasopressin in penile deep dorsal
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TABLE 1
Maximal responses and pD2 values to vasopressin and pA2 and slope
values of Schild plots of the antagonism of d(CH2)5Tyr(Me)AVP (V1
antagonist) in human penile dorsal arteries and veins
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Segarra et al.
Vol. 286
Fig. 3. Inhibition
by
the
V1
antagonist
d(CH2)5Tyr(Me)AVP (3 3 1029-1027 M) of the potenti211
ation induced by 10
M vasopressin on electrical
stimulation-induced responses.
Fig. 5. Contractile responses to electrical stimulation in the absence and
in the presence of increasing concentrations (10210-1028 M) of the V2
receptor agonist desmopressin.
artery and vein. Antagonists of arginine vasopressin have
been used to study the vascular effects of this peptide and to
characterize the receptors involved (Sawyer et al., 1981).
Furthermore, these antagonists have been reported to be
potent inhibitors of the contractile response of human corpus
spongiosum to vasopressin (Andersson et al., 1987). We demonstrate that d(CH2)5Tyr(Me)AVP inhibited the vasopressin
contraction in a competitive way over a given concentration
range of the antagonist. Schild analysis showing unitary
slopes and antagonist pA2 values obtained from these data
indicate that the receptors involved in vasopressin induced
contraction belong to the classical V1 receptors (Sawyer and
Manning, 1985). Similar pA2 values for the same V1 antagonist have been found in human uterine arteries (Jovanovic
Fig. 6. Frequency-response relationship in the absence and in the presence of cocaine (1026 M) or cocaine together with vasopressin (10211 M)
*P , .05 vs. control.
et al., 1995) and in several vascular beds of the rabbit (Garcı́a-Villalón et al., 1996).
The present study also shows that low concentrations of
vasopressin enhance the contractile effects of electrical stimulation and norepinephrine. The potentiating effects occur at
vasopressin concentrations lower than those required to produce a clear direct contractile response.
We examined the potential role of V2 receptor stimulation
in the enhancing effects of vasopressin. The results do not
support the intervention of V2 receptors in these responses.
First, the selective V2 agonist desmopressin did not modify
responses to vasopressin or to electrical field stimulation. On
the
other
hand,
the
V2
receptor
antagonist
[d(CH2)5,D,Ile2,Ile4,Arg8]vasopressin did not affect the potentiation induced by vasopressin. In contrast, the selective
V1 receptor antagonist d(CH2)5Tyr(Me)AVP inhibited the po-
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Fig. 4. Bar graphs showing effects of
10211 M vasopressin on frequency-dependent contractile responses to electrical
field stimulation in the absence and in
the presence of 3 3 1028 M V1 antagonist
d(CH2)5Tyr(Me)AVP. *P , .05 vs. control.
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Vasopressin and Human Penile Blood Vessels
Fig. 7. Concentration-response curves to norepinephrine in the absence
(F) and in the presence of vasopressin (f, 3 3 10211 M) and in the
presence of the V1 receptor antagonist (3 3 1028 M) together with vasopressin (E).
Norepinephrine
pD2
Maximal
response
%
Control
Artery (n 5 6)
Vein (n 5 6)
With vasopressin 3 3 10211 M
Artery (n 5 6)
Vein (n 5 6)
With V1 antagonist 3 3 1028 M 1
vasopressin
Artery (n 5 6)
Vein (n 5 6)
6.43 6 0.12
6.79 6 0.14
156 6 9
135 6 7
7.16 6 0.21a
7.31 6 0.14a
155 6 13
144 6 7
6.56 6 0.16
6.85 6 0.14
152 6 9
132 6 5
Values are mean 6 S.E. Maximal contractions are expressed as a percentage of
response to 100 mM KCl.
a
P , .05 compared with control rings.
n, number of patients.
tentiating effects of vasopressin on electrical field stimulation and norepinephrine- induced contraction in a concentration-dependent manner. Therefore, the results exclude a role
for V2 receptors in the potentiating effects of vasopressin and
they are consistent with the hypothesis that V1 receptor
stimulation by vasopressin in the absence of direct contraction is followed by enhancement of responses to both endogenous and exogenous norepinephrine.
It might be conceived that the effects of vasopressin on
electrical stimulation contractions could involve an effect on
adrenergic nerves leading to release of norepinephrine or
alternatively, vasopressin could act with norepinephrine at
postjunctional receptor sites. Because norepinephrine release was not measured in this study, a contribution of
prejunctional facilitating effects cannot be excluded. The fact
that the concentration response curves to vasopressin were
not modified by prazosin, an a1-adrenoceptor blocker, suggests that the action of this peptide does not involve release
of norepinephrine. The possibility that vasopressin could
block the reuptake of norepinephrine and therefore enhance
the contractile response is unlikely because the potentiating
effects were still evident in the presence of cocaine. In the
conditions of our experiments, cocaine per se failed to potentiate the vasoconstriction produced by nerve stimulation, a
finding similar to that recently observed in human saphenous vein (Medina et al., 1998). This suggests that neuronal
reuptake of norepinephrine in these vessels is of little impor-
tance, a circumstance that is mainly dependent on vascular
region and species (Berkowitz et al., 1971; De la Lande et al.,
1967; Lluch et al., 1975).
It has been shown that human corpus cavernosum and
corpus spongiosum contain vasopressin in concentrations
higher than those normally found in the circulation (Andersson et al., 1987). This was interpreted to indicate that the
hormone might be synthetized locally or taken up and stored
(Kasson and Hsueh, 1986; Andersson et al., 1987). Such a
circumstance, together with the potent contractile effects of
vasopressin on penile vessels may lead to speculate that
vasopressin may act as a cotransmitter. If vasopressin is
released together with norepinephrine from adrenergic
nerves and contributes to the contractile effects of nerve
stimulation, V1 antagonists should partially block these contractile effects. The V1 antagonist effectively blocked vasopressin contractions, but electrically-induced contractions
were unaffected. Another possible explanation for the vasopressin induced potentiation is a change at the receptor level
leading to an increased affinity of norepinephrine for its
receptor. This may be a likely explanation, because vasopressin increased the contractions to exogenous applied norepinephrine. Thus our data are consistent with the suggestion
that potentiation of the effects of nerve stimulation by vasopressin corresponds to a postsynaptic enhancement of the
action of norepinephrine.
Stimulation of the lumbar sympathetic chain produces detumescence or inhibition of erection in various animal species
(Carati et al., 1987; Diederichs et al., 1991; Giuliano et al.,
1993). Therefore the flaccid state of the penis has been considered to depend on activation of adrenergic nerves. Although vasopressin does not seem to act as a co-transmitter
with norepinephrine in these vessels, the recent discovery
that vasopressin may be synthetized by vascular smooth
muscle cells (Simon and Kasson, 1995) raises the possibility
that locally released vasopressin may reach concentrations
high enough to induce penile vasoconstriction and act synergistically with the adrenergic neurotransmitter. The concentrations of vasopressin in this study would be expected to be
similar to basal plasma concentrations in normal humans
(Harada et al., 1991; Hirsch et al., 1989) and lower than those
observed in response to hypotension, dehydration, exercise,
and in some patients with hypertension or congestive heart
failure (Melin et al., 1980; Nicod et al., 1985; Sorenson and
Hammer, 1985). Consequently, the direct contractile effects
of vasopressin together with its amplifying effects on adrenergic-mediated constriction should be taken into consideration in the overall regulation of penile erection and in those
states characterized by increased plasma vasopressin levels.
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