Download Yohimbine enhances the effect of sildenafil on erectile

International Journal of Impotence Research (2008) 20, 409–417
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ORIGINAL ARTICLE
Yohimbine enhances the effect of sildenafil on erectile process in
rats
AM Senbel1 and T Mostafa2
1
Pharmacology Department, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt and 2Andrology and
Sexology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Combining the centrally acting drug yohimbine with the peripheral conditioner sildenafil might be
an approach to erectile dysfunction cases in which sildenafil alone failed. This work aimed to
investigate the effect of yohimbine on sildenafil-induced facilitation of erectile process. Erectile
responses to electrical stimulation of the cavernous nerve in anesthetized male rats were recorded.
Intracavernosal pressure/systemic arterial pressure (ICP/SAP) was calculated, 1 and 5 min after
intravenous administration of sildenafil, yohimbine or a combination of both. Changes in sexual
arousal and copulatory performance indices were compared before and after these injections using
behavioral mating experiments. It was shown that systemic administration of sildenafil produced a
significant increase in ICP/SAP than control at doses X10 lmol kg1. Yohimbine alone failed to
potentiate erectile responses but yohimbine (1 lmol kg1) significantly potentiated the effect of
sildenafil 1–10 lmol kg1 and 1 mmol kg1, 1 and 5 min after injection. Potentiation of ICP/SAP
induced by their combination was greater than the sum of the effects of the corresponding doses of
either drug at the same time interval. A nonsignificant additional decrease in SAP than sildenafilinduced was observed if administered with yohimbine. Addition of sildenafil to yohimbine
significantly enhanced the effect of the latter on intromission frequency, intercopulatory interval
and the number of ejaculations per session. It is concluded that yohimbine may enhance and
prolong the effect of sildenafil on erectile process without additional hypotension. Sildenafil may
enhance the central effects of yohimbine on erection; it amplifies the effect of yohimbine on male
copulatory performance but not on sexual motivation. The potential beneficial effect of the
combination was found to be more pronounced on the central component than on the peripheral
component of the erectile process.
International Journal of Impotence Research (2008) 20, 409–417; doi:10.1038/sj.ijir.3901630;
published online 17 April 2008
Keywords: erectile dysfunction; sildenafil; yohimbine; phosphodiesterase inhibitor; corpus
cavernosum
Introduction
Sexual behavior and erectile function are influenced
by emotional and cognitive functions. At the central
nervous system level hypothalamic and limbic
systems are responsible for central erectogenic
signals facilitating spinal cord pathways, which
lead to erection via peripheral autonomic nerves.1
Current strategies for the pharmacological treatment
of erectile dysfunction (ED) favor the use of oral
Correspondence: Professor Dr T Mostafa, Andrology and
Sexology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
E-mail: [email protected]
Received 27 December 2006; revised 28 September 2007;
accepted 25 October 2007; published online 17 April 2008
agents, including the PDE5 inhibitors, phentolamine, yohimbine, L-arginine and so on.1,2
Introduction of sildenafil citrate (Viagra Pfizer
Inc., New York, NY, USA) in 1998, has been an
advancement in improving erectile function and
enabling successful sexual intercourse in men with
broad spectrum ED.3,4 Yohimbine is an indole
alkaloid whose aphrodisiac activity may be
mediated through a combination of central nervous
system effects and peripheral effects including
blockade of pre- and postsynaptic a2-adrenergic
receptors.5–7 Placebo-controlled studies have suggested the effectiveness of yohimbine in treating ED
due to psychogenic or mild organic etiology, but the
outcome of its use was, however, disappointing.8
Since the advent of sildenafil, there has been a
resurgence of interest in ED and an increase in
patients presenting with this disease.9 However,
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
410
several studies showed that administering sildenafil
could not result in rigidity sufficient for satisfactory
sexual intercourse in 11–22% of patients with
psychogenic and 36–65% with organic ED.10,11
Combination drug therapy seems appealing to treat
patients with ED in whom monotherapy with
sildenafil failed. Therefore, combining the centrally
acting drug yohimbine with the peripheral conditioner sildenafil might be an attractive approach.
This study therefore was designed to investigate the
effect of yohimbine on sildenafil-induced facilitation of centrally and peripherally mediated erectile
process in male rats.
Materials and methods
Animals
Experiments were carried out on male albino rats
200–350 g weight (approximately aged 4–6 months)
and female albino rats 150–200 g. All animals used
were bred in the animal house at the Faculty of
Pharmacy according to NIH guidelines, housed
under constant environmental conditions, fed diets
consisting of wheat or bread soaked in milk. Water
was allowed ad libitum.
Measurement of ICP in rats
Experiments have been conducted by measuring
intracavernosal pressure (ICP) changes elicited
by electrical stimulation of the cavernosal
nerve (CN) in anesthetized rats according to the
method described by Giuliani et al.12 Male rats were
anesthetized by intraperitoneal injection of thiopental (50 mg kg1), then the skin overlying the penis
was incised, and the prepuce was degloved to
expose the corpora cavernosa. A 26-gauge needle
filled with heparinized saline was carefully inserted
into the corpus cavernosum on one side to measure
ICP. The needle was sealed to a polyethylene 50
tubing of 20 cm length filled with heparinized
saline, connected to a Gould-Statham pressure
transducer (Oxnard, CA, USA). ICP was displayed
on a Grass polygraph (Model 7D, Grass Inst. Co.,
MA, USA).
Through a lower suprapubic midline incision, the
lateral prostate was dissected and the major pelvic
ganglion was identified. The CN was unilaterally
freed from its facial attachments and stimulated
electrically using a bipolar platinum electrode
placed 3–4 mm distal to the major pelvic ganglion.13
The two poles of the electrode were separated by
2 mm and the electrode was connected to an
electronic stimulator (Letica, Panlab, Model 12106/
150, Spain). CN was stimulated for 1 min, the pulse
parameters were 5 V, 1 ms duration and 0.5–10 Hz
frequency. Maximum rise in ICP during nerve
stimulation was measured. ICP/SAP ratio (ICP is
International Journal of Impotence Research
computed at the maximal effect after CN stimulation
and SAP is the systemic arterial pressure computed
at the same time) was calculated. ICP/SAP 1 and
5 min after intravenous (i.v.) administration of the
drug were compared to control cavernous responses
in the same rat. Percentage potentiation in ICP
induced by the combinations was then statistically
compared to that induced by every drug alone in the
previous set of experiments at the same time
interval. In this set of experiments, the drug(s) and
drug combinations were administered i.v.; the effect
was recorded 1 and 5 min after injection. A catheter
was inserted into the femoral vein and used for i.v.
drug administration. A time-matched control using
saline vehicle was performed alongside with the
original experiment.
Intravascular cannulation and measurement of
blood pressure
Measurement of blood pressure and heart rate in rats
was made as described previously by Tseng et al.14
About 1 cm incision was made in the skin of the
groin and the underlying muscles were cut, then the
femoral artery and vein were exposed and freed
from underlying muscles. By a fine scissors or a 901
curved needle, a small incision was made in the
artery near a closed tie through which a polyethylene catheter, 20 cm length filled with heparinized
saline, was introduced. The arterial catheter
was connected to the pressure transducer and
arterial blood pressure was displayed on a Grass
polygraph.
Behavioral testing in rats
Copulatory behavioral tests on rats were performed
as described previously by Butcher et al.15 Male and
female rats were housed at room temperature for 1
week before the start of the experimental period,
three or four to a cage. All experiments were
performed between 1100 and 1500 hours in a sound
attenuated room.16 Sexual activity of rats was
evaluated after four selection mating tests with
receptive females. After selection tests, animals
were admitted to the experimental session if they
had exhibited at least one ejaculation per test.17 The
normal coital pattern in male rats is characterized by
the following behavioral sequence: (1) mounting
of the female followed by a penile intromission
lasting approximately 1/3 s, (2) withdrawal of the
penis and dismount and (3) a brief rest interval of
about 40–60 s. This sequence is then repeated
several times until ejaculation occurs with the
terminal intromission of the series. Ejaculation was
identified by vigorous thrush and longer intromission period, and was always followed by a
resting period (post-ejaculatory interval (PEI)) of
10–15 min.15
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
Estrous was induced in the stimulus female by
means of a combined treatment of estrogen and
progesterone. Forty-eight hours before testing, the
females were subcutaneously injected with
60 mg kg1 estradiol benzoate followed by 1 mg kg1
progesterone 4 h prior the observation period. After
a 10-min adaptation period in the observation cage,
a receptive female was presented to the male by
dropping it gently into the cage. By direct observation, the following behavioral parameters were
recorded:
(1) mount latency (ML): the time from introduction
of the female to the occurrence of the first mount;
(2) intromission latency (IL): the time from introduction of the female to the occurrence of the
first intromission;
(3) ejaculation latency (EL): time from the first
intromission to ejaculation;
(4) PEI: time from ejaculation to the subsequent
intromission;
(5) intromission frequency (IF): number of intromissions preceding ejaculation;
(6) ejaculation frequency (EF): number of ejaculation in a session; and
(7) intercopulatory interval (ICI): average interval
between successive intromissions (EL/IF).
Testing sessions lasted 30 min. Each male animal
served as its own control. Each rat was used
only twice, one time as a control and the second
(after at least 48 h) as treated. The drug, combination
or vehicle (saline) was injected intraperitoneally
1 h before the testing session. The time between
the two periods (control and treated) should be at
least 48 h.
Statistics
Values were expressed as mean±s.e.m. Student’s
t-test was used for the analysis of paired data. For
multiple comparison, one-way analysis of variance
(ANOVA or F-test) followed by Dunnet or Student–
Newman–Keuls post-test was performed. The criterion for statistical significance was set at the 0.05
level. Throughout the manuscript ‘n’ indicates the
number of rats.
411
Results
Effect of sildenafil on nerve-stimulated erectile
responses
This set of experiments began with 3–5 CN stimulations at different frequencies to select a suitable
frequency that produced a submaximal increase in
ICP. The submaximal frequency (usually lying
between 1 and 6 Hz) was then repeated twice; a
reproducible response was to be obtained. The drug
under test was then injected i.v. and the cavernous
responses to CN stimulation were recorded for 5 min
after drug administration (Figure 1). Sildenafil
produced potentiation of neurogenic erectile response at all concentrations used with significant
levels attained at concentrations X10 mmol kg1.
Electrical stimulation of the CN produced an ICP/
SAP value of 0.413±0.075 mm Hg in the presence of
1 mmol kg1 sildenafil compared with 0.095±
0.016 mm Hg in its absence 1 min after i.v. injection,
n ¼ 8 (Figure 2).
Effect of yohimbine on nerve-stimulated erectile
responses
Yohimbine (0.1 mmol kg1 to 1 mmol kg1) failed to
increase ICP/SAP significantly compared to control
values, neither at 1 min nor at 5 min after i.v.
injection, n ¼ 7 (Figure 3).
Effect of sildenafil/yohimbine combinations on
nerve-stimulated erectile responses
ICP rise in response to electrical stimulation of the
CN was recorded before and after the i.v. injection of
combinations of yohimbine 1 mmol kg-1 with increasing doses of sildenafil (1 mmol kg1 to 1 mmol kg1).
The effect of all combinations tested was significantly greater than the effect of yohimbine alone.
Figure 1 Representative tracing showing the effect of intravenous administration of sildenafil on changes of intracavernosal pressure
and mean systemic arterial pressure associated with cavernous nerve-stimulated penile erection in anesthetized rats.
International Journal of Impotence Research
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
412
Figure 2 Effect of i.v. sildenafil (1 mmol kg1 to 1 mmol kg1) on erectile responses to electrical stimulation of the cavernous nerve, 1 min
(a) and 5 min (b) after injection. Results are expressed as mean±s.e.m. of eight experiments. *Denotes significant difference compared to
control at the level of Po0.05. ICP, intracavernosal pressure; i.v., intravenous; SAP, systemic arterial pressure.
Figure 3 Effect of i.v. yohimbine (0.1 mmol kg1 to 1 mmol kg1) on erectile responses to electrical stimulation of the cavernous nerve,
1 min (a) and 5 min (b) after injection. Results are expressed as mean±s.e.m. of seven experiments. ICP, intracavernosal pressure; i.v.,
intravenous; SAP, systemic arterial pressure.
One minute after i.v. administration, percentage
potentiation of ICP/SAP induced by a combination
of 10 mmol kg1 sildenafil and 1 mmol kg1 yohimbine was significantly greater than the effect of
sildenafil alone and that of the algebraic sum of
individual effects, indicating a synergistic action.
Similar action was observed with a higher dose
combination (1 mmol kg1 sildenafil and 1 mmol kg1
yohimbine) 5 min after injection, n ¼ 7 (Figure 4).
Effect of sildenafil, yohimbine and sildenafil/
yohimbine combination on mating behavioral
parameters
Intraperitoneal injection of yohimbine (1 mmol kg1),
n ¼ 8 in male rats increased sexual motivation
parameters. It significantly reduced ML, EL, PEI
and ICI compared to control values. Sildenafil
(10 mmol kg1, n ¼ 8) significantly reduced time to
the first intromission and ejaculation. Sildenafil
showed a facilitator effect on erection with significant reduction in intromissions required to achieve
ejaculation. Percent change (potentiation or inhibition) of each of the mating parameters induced by
International Journal of Impotence Research
their combination was calculated and statistically
compared to that of sildenafil alone, yohimbine alone
and that of the algebraic sum of their individual
effects. The effect of combination (1 mmol kg1
yohimbine þ 10 mmol kg1 sildenafil, n ¼ 8) on intromission frequency and ICI was significantly different
from the effect of yohimbine alone. Combining low
doses of sildenafil and yohimbine added a further
advantage: a potentiation of the number of erections/
session compared to none for either sildenafil or
yohimbine alone (Figures 5–7).
Effect on SAP
For each i.v. injection, the SAP (mm Hg) was
measured directly at the time of injection as well
as 1 and 5 min after administration of the drug(s).
Values were then compared to basal blood pressure
values just before injection. The reduction in SAP
induced by sildenafil was more pronounced than
that induced by yohimbine, especially at high doses.
Combinations of drugs tested did not produce a
further decrease in SAP, compared to the additive
effect of sildenafil and yohimbine (Table 1).
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
413
Figure 4 Effect of sildenafil (1 mmol kg1 to 1 mmol kg1), yohimbine (1 mmol kg1) and their combination on erectile responses to
electrical stimulation of the cavernous nerve, 1 min (a) and 5 min (b) after injection. Values are expressed as mean±s.e.m. of seven
experiments. $Denotes significant difference compared to sildenafil group at the level of Po0.05, #denotes significant difference
compared to yohimbine group at the level of Po0.05 and *denotes significant difference compared to the sum of individual effects at the
level of Po0.05. ICP, intracavernosal pressure; SAP, systemic arterial pressure.
Figure 5 Effect of yohimbine (1 mmol kg1) on different copulatory parameters in male rats. Values are expressed as mean±s.e.m. of
eight experiments. Rats were injected intraperitoneally with the drug 1 h before the 30 min experimental session. *Denotes significant
difference compared to control at the level of Po0.05.
Discussion
In the in vivo rat model where erection is induced by
electrical stimulation of the CN, i.v. administration
of sildenafil (10 mmol kg1 to 1 mmol kg1) dose
dependently increased ICP significantly compared
to the control values. The current results are
in agreement with previous reports, sildenafil
was demonstrated to facilitate neurogenic penile
erections in rabbits18 and dogs,19 and are also in line
with the previously described results in anesthe-
tized rats.20 When sildenafil was tested alone, it
succeeded to significantly reduce IL indicating a
moderate potentiatory effect on sexual motivation,
although the other sexual motivation-driven parameters (ML, PEI and ICI) were unaltered. EL and
number of intromissions preceding ejaculation were
significantly reduced by the action of sildenafil in
rats, indicating a beneficial effect on copulatory
performance, may be next to the peripheral facilitatory effect of sildenafil on erection. However,
when tested in combination with yohimbine, both
International Journal of Impotence Research
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
414
Figure 6 Effect of sildenafil (10 mmol kg1) on different copulatory parameters in male rats. Values are expressed as mean±s.e.m. of
eight experiments. Rats were injected intraperitoneally with the drug 1 h before the 30 min experimental session. *Denotes significant
difference compared to control at the level of Po0.05.
Figure 7 Comparison of the effect of sildenafil (10 mmol kg1),
yohimbine (1 mmol kg1) and sildenafil/yohimbine combination
on mount latency (ML), intromission latency (IL), ejaculation
latency (EL), post-ejaculatory interval (PEI), intromission frequency (IF), ejaculation frequency (EF) and intercopulatory
interval (ICI) in male rats. Values are expressed as mean±s.e.m.
of eight experiments. Rats were injected intraperitoneally with
the combination 1 h before the 30 min experimental session.
$
Denotes significant difference compared to the sildenafil group
at the level of Po0.05, #denotes significant difference compared
to the yohimbine group at the level of Po0.05 and *denotes
significant difference compared to the sum of individual effects at
the level of Po0.05.
injected intraperitoneally, it reduced mount, intromission and ELs and ICI, indicating an increase in
arousal and motivation. The combination potently
International Journal of Impotence Research
decreased the intromission frequency and increased
number of ejaculations per session indicating an
increase in copulatory performance and potency.
The synergistic effect of this combination on sexual
and copulatory behaviors may be attributed to the
combination of the peripheral effects of sildenafil on
erectile function with the central effect of yohimbine and sildenafil, to a lesser extent, on male sexual
behaviors. Giuliani et al.21 reported that sildenafil
acts not only peripherally but also centrally since
oral administration of sildenafil (1 mg kg1) in rats
modified both sexual and ejaculatory mechanisms
of copulation. However, it was demonstrated that
sildenafil did not improve sexual function in men
without ED and it did not induce erections in young
healthy men.22 The moderate results of sildenafil on
mating parameters, as demonstrated in the present
study, are consistent with the low expression of
PDE5 in the brain, as the most widely expressed PDE
isozymes in the brain are PDE1 and 2, which are
related to memory.23 Some investigators reported
that sildenafil enhanced object recognition memory
and that vardenafil increased cGMP concentrations
in neural fibers of the hippocampal region in rats.24
As for yohimbine, it failed to peripherally modulate erectile functions; it did not potentiate
neurogenic erections after systemic administration
in rats. Previous studies demonstrated that yohimbine potently relaxed phenylephrine precontracted
strips of rabbit corpus cavernosum.25 Consequently,
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
415
Table 1 Effect of sildenafil, yohimbine and sildenafil/yohimbine combination on SAP
Treatment
Sildenafil 10 mmol kg1 (8)
Yohimbine 1 mmol kg1 (7)
Combination (7)
Sildenafil 1 mmol kg1 (8)
Yohimbine 1 mmol kg1 (7)
Combination (7)
Decrease in SAP (mm Hg)
At time of injection
1 min after injection
5 min after injection
6.333±0.718
3.50±1.345
4.40±0.624
27.50±1.058* (Po0.0001)
3.50±1.345* (Po0.0001)
16.8±0.937
0.916±0.49* (P ¼ 0.036)
1.25±0.496
2.80±0.654
4.67±0.452* (P ¼ 0.0059)
1.25±0.496* (P ¼ 0.0219)
2.80±0.318
1.08±0.042
1.25±0.283
1.40±0.906
1.75±0.074* (P ¼ 0.0162)
1.25±0.283* (P ¼ 0.0082)
2.80±0.40
Abbreviation: SAP, systemic arterial pressure.
Values are expressed as mean±s.e.m. Values in parentheses in column 1 indicate number of experiments.
*Indicates statistical difference in comparison to the combination group.
it could be expected that yohimbine would induce
erection in absence of sexual stimulation; however,
contrary results were obtained in this study. This
effect has not been reported in vivo in animals or in
humans. Yohimbine had no effect on erectility when
given intracavernosally in humans.26 However,
yohimbine, in a few number of combinations tested
in the current study, was able to enhance the effect
of sildenafil synergistically on erectile responses
induced by electrical stimulation of the CN. In
combination with yohimbine, the potentiatory effect
of a higher dose of sildenafil was prolonged. Maggi
et al.2 indicated that yohimbine is a mixed a1- and
a2-adrenergic receptor antagonist. It seems from the
latter study that a1-receptors antagonism predominates at high doses since yohimbine (1 108 and
1 107 M) enhanced electrically induced contractions in isolated corpus cavernosum while
1 106 M inhibited them.27 The possible peripheral events following yohimbine administration
have been reported to be as follows: (1) inhibition
of the binding to post-junctional a2-receptors attenuating contraction mediated by norepinephrine (NE);
(2) inhibition of pre-junctional a2-receptors on the
adrenergic nerves resulting in an increase in the
release of NE and (3) inhibition of the binding to
pre-junctional a2-receptors in the nonadrenergic
noncholinergic nerves decreasing the release of
NO.28 The two latter mechanisms could be expected
to be the cause behind the modest effect of
yohimbine observed on ICP. On the other hand, the
effect of some high doses of sildenafil on ICP
increases in response to electrical stimulation was
inhibited by combination with yohimbine. No data
in literature about the mechanism of action of
sildenafil could explain this ‘negative synergism’,
which remains a limitation of this study. Further
studies are needed to elaborate and explain this
observation.
The effect of yohimbine on erectile function
seems to be mostly centrally mediated, since in the
present study, its acute intraperitoneal injection
reduced mount and ejaculation latencies, ICI and
PEI, reflecting an increase in sexual motivation.
These results are in line with previous studies in
animals showing that the drug has a remarkable
positive effect on sexual performance.29–31 It is
reported that yohimbine facilitates sexual arousal
by acting on a2-adrenergic receptors in central
nervous system.2,32,33 Interestingly, yohimbine may
stimulate serotonin receptors in the brain,32 and
enhanced serotoninergic transmission is reported to
stimulate oxytocin secretion in the blood of male
rats, which in turn enhances sexual behavior and
erection.34 Furthermore, it was suggested that the
dopaminergic system might be the final pathway for
yohimbine-induced behavior expression.35
At all doses tested, sildenafil decreased blood
pressure directly after injection in agreement with
the clinical studies of sildenafil in humans. After
single therapeutic doses, there was a non-dosedependent mild and transient decrease in blood
pressure not associated with a significant effect on
heart rate.36 In another clinical trial, sildenafil was
reported to have a modest effect on blood pressure
in normal subjects, producing an average decrease of
about 10 mm Hg after a single oral dose of 100 mg.37
Yohimbine-induced hypotension was short in
duration in low doses but long-lasting with higher
ones. Consistently, Lang et al.38 reported that i.v.
administration of yohimbine in rats caused a
decrease in blood pressure and an increase in heart
rate. Similar results were reported in cats.39 Clinical
studies revealed controversial results. One study
reported that yohimbine increased blood pressure in
volunteers by 15–20 mm Hg,40 while others showed
that it did not significantly affect heart rate
and blood pressure in normotensive subjects.41 It
seems that the effect of yohimbine on cardiovascular
functions in human are minimal in relation to
those observed in rats. One of the advantages
of the suggested sildenafil/yohimbine combination
is that no excessive hypotension was induced
after i.v. administration. The effect of all combinations tested on systemic blood pressure was
always lower than the algebraic sum of the
corresponding doses of sildenafil and yohimbine
when given alone.
International Journal of Impotence Research
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
416
In a similar attempt to study the effect of
combining yohimbine with a NO conditioner, Lebret
et al.42 demonstrated that on-demand administration of 3.25 g of the NO precursor L-arginine and
6 mg yohimbine, administered 1–2 h before intended
sexual intercourse, significantly improved erectile
function in patients with mild-to-moderate ED. The
results of the current study, which still have to be
tested clinically, demonstrate that combining sildenafil and yohimbine for the management of ED may
be beneficial.
It is concluded that yohimbine may enhance and
prolong the effect of sildenafil on the erectile
process in rats without causing concomitant hypotension. Sildenafil may enhance the central effects
of yohimbine on erection: the potential beneficial
effect of the combination was more pronounced on
the central component (sexual behavior) than on the
peripheral component of the erectile process. Sildenafil amplifies the effect of yohimbine on male
copulatory performance but not on male sexual
motivation. Therefore, the use of lower doses of
sildenafil combined with yohimbine may present a
potential advantage in treating ED cases that do not
respond to sildenafil alone.
14
15
16
17
18
19
20
21
22
References
23
1 Bivalacqua TJ, Champion HC, Hellstrom WJ, Keadowitz PJ.
Pharmacotherapy for erectile dysfunction. Trends Pharmacol
Sci 2000; 21: 484–489.
2 Maggi M, Filippi S, Magini A, Forti G. Erectile dysfunction:
from biochemical pharmacology to advances in medical
therapy. Eur J Endocrinol 2000; 143: 143–154.
3 Langtry HD, Markham A. Sildenafil: a review of its use in
erectile dysfunction. Drugs 1999; 57: 967–989.
4 Goldstein I, Lue TF, Padma-Nathan H. Oral sildenafil in the
treatment of erectile dysfunction. N Engl J Med 1998; 338:
1397–1404.
5 Guay AT, Spark RF, Jacobson J, Murray FT, Geisser ME.
Yohimbine treatment of organic erectile dysfunction in a doseescalation trial. Int J Impot Res 2002; 14: 25–31.
6 Kandeel FR, Koussa VK, Swerdloff S. Male sexual function
and its disorders: physiology, clinical investigation, and
treatment. Endocrine Rev 2001; 22: 342–388.
7 McKay D. Nutrients and botanicals for erectile dysfunction:
examining the evidence. Altern Med Rev 2004; 9: 4–16.
8 Kuneluis P, Hakkinen J, Lukkarinen O. Is high-dose yohimbine
hydrochloride effective in the treatment of mixed type
impotence? A prospective, randomized, controlled double
blind crossover study. Urology 1997; 49: 441–444.
9 Lue TF. Erectile dysfunction. N Engl J Med 2000; 342:
1802–1813.
10 McMahon CG, Samali R, Johnson H. Efficacy, safety and
patient acceptance of sildenafil citrate as treatment for erectile
dysfunction. J Urol 2000; 164: 1192–1196.
11 Wagner G, Saenz De Tejada I. Update on male erectile
dysfunction. Br Med J 1998; 316: 678–682.
12 Giuliani D, Bernabe J, Jardin A, Rousseau JP. Antierectile role
of the sympathetic nervous system in rats. J Urol 1993; 150:
519–524.
13 Zvara P, Spiess PE, Merlin SL, Begin LR, Brock GB.
Neurogenic erectile dysfunction: the course of nicotinamide
adenine dinucleotide phosphate diaphorase-positive nerve
24
International Journal of Impotence Research
25
26
27
28
29
30
31
32
33
fibers on the surface of the prostate. Urology 1996; 47:
146–151.
Tseng CJ, Liu HY, Lin HC, Ger LP, Tung CS, Yen MH.
Cardiovascular effects of nitric oxide in the brain stem nuclei
of rats. Hypertension 1996; 27: 36–42.
Butcher LL, Butcher SG, Larsson K. Effects of apomorphine,
amphetamnine, and nialiamide on tetrabenazine-induced
suppression of sexual behavior in the male rat. Eur J
Pharmacol 1969; 7: 283–288.
Drago F, Busa L, Benelli A, Bertilini A. Acute low doses of
melatonin stimulate sex behavior: the role of serotonin
neurotransmission. Eur J Pharmacol 1999; 385: 1–6.
Giuliani D, Ferrari F. Differential behavioral response to
dopamine D2 agonists by sexually naı̈ve, sexually active
and sexually inactive male rats. Behav Neurosci 1996; 110:
802–804.
Choi S, O’connell L, Min K, Kim NN, Munarriz R, Goldstein I
et al. Efficacy of vardenafil and sildenafil in facilitating
penile erection in an animal model. J Androl 2002; 23:
123–128.
Carter AJ, Ballard SA, Naylor AM. Effect of the selective
phosphodiesterase type 5 inhibitor sildenafil on erectile
function in the anesthetized dog. J Urol 1998; 160: 242–246.
Ueno N, Iwamoto Y, Segawa N, Kinoshita M, Ueda H,
Katsuoka Y. The effect of sildenafil on electrostimulationinduced erection in the rat model. Int J Impot Res 2002; 14:
251–255.
Giuliani D, Ottani A, Ferrari F. Influence of sildenafil on
copulatory behavior in sluggish or normal ejaculator male rats:
a central dopamine mediated effect? Neuropharmacol 2002;
42: 562–567.
Gemalmaz H, Waldeck K, Chapman TN, Tuttle JB, Steers WD,
Andersson KE. In vivo and in vitro investigation of the effects
of sildenafil on rat cavernous smooth muscle. J Urol 2001; 165:
1010–1014.
Baevo JA. Cyclic multiple isoforms. Physiol Rev 1995; 75:
725–748.
Prickaerts J, van Staveren WC, Sik A, Markerink-van Ittersum
M, Niewohner U, van Der Staay FJ et al. Effects of two
selective phosphodiesterase type 5 inhibitors, sildenafil
and verdenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience 2002; 113:
351–361.
Sharabi FM, Daabees TT, El-Metwally MA, Senbel AM.
Comparative effects of sildenafil, phentolamine, yohimbine
and L-arginine on the rabbit corpus cavernosum. Fundam Clin
Pharmacol 2004; 18: 187–194.
Brindley GS. Pilot experiments on the actions of drugs
injected into the human corpus cavernosum penis. Br J
Pharmacol 1986; 87: 495–498.
Mizusawa H, Hedlund P, Sjunnesson J, Brioni JD,
Sullivan JP, Andersson KE. Enhancement of apomorphineinduced penile erection in the rat by a selective
alpha(1D)-adrenoceptor antagonist. Br J Pharmacol 2002;
136: 701–708.
Lue T, Goldstein I, Traish A. Comparison of oral and
intracavernosal vasoactive agents in penile erection. Int J
Impot Res 2000; 12(Suppl. 1): S81–S88.
Rampin O. Pharmacology of alpha-adrenoceptors in male
sexual function. Eur Urol 1999; 1: 103–106.
Morales A, Condra M, Owen JA, Surridge DH, Fenemore J,
Harris C. Is yohimbine effective in treatment of organic
impotence? Results of a controlled trial. J Urol 1987; 137:
1169–1172.
Yonezawa A, Ando R, Imai M, Watanabe C, Furuta S, Kutsuwa M
et al. Differential effects of yohimbine, naloxone and 8-OHDPAT on ejaculatory response in male dogs.. Methods Find
Exp Clin Pharmacol 2004; 26: 47–51.
Traish A, Kim NN, Moreland RD, Goldstein I. Role of alpha
adrenergic receptors in erectile function. Int J Impot Res 2000;
12: S48–S63.
Papeschi R, Sourkes TL, Youdim MBH. The effect of
yohimbine on brain serotonin metabolism, motor behavior
Combined effect of yohimbine and sildenafil
AM Senbel and T Mostafa
34
35
36
37
and body temperature of the rat. Eur J Pharmacol 1971; 15:
318–326.
Saydoff JA, Rittenhouse PA, Van De Kar LD, Brownfield MS.
Enhanced serotoninergic transmission stimulates oxytocin
secretion in conscious male rats. J Pharmacol Exp Ther
1991; 257: 95–99.
Rodriguez-Manzo G. Yohimbine interacts with the dopaminergic system to reverse sexual satiation: further evidence for
a role of sexual motivation in sexual exhaustion. Eur J
Pharmacol 1999; 372: 1–8.
Jackson G, Benjamin N, Jackson N, Allen M. Effects of
sildenafil citrate on human hemodynamics. Am J Cardiol
1999; 83: 13C–20C.
Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil
citrate and blood-pressure-lowering drugs: results of drug
interaction studies with an organic nitrate and a calcium
antagonist. Am J Cardiol 1999; 83(5A): 21C–28C.
38 Lang WJ, Lambert GA, Rush ML. The role of the central
nervous system in the cardiovascular responses to yohimbine.
Arch Int Pharmacodyn 1975; 217: 57–67.
39 Abdel Rahman ARA, Sharabi FM. Presynaptic alpha
receptors in relation to the cardiovascular effect of yohimbine
in the anesthetized cat. Arch Int Pharmacodyn 1981; 252:
229–240.
40 Susset JG, Tessier CD, Wincze J, Bansal S, Malhotra C,
Schwacha MG. Effect of yohimbine hydrochloride on erectile
impotence: a double-blind study. J Urol 1989; 141: 1360–1363.
41 Ernst E Pittler MH. Yohimbine for erectile dysfunction: a
systematic review and meta-analysis of randomized clinical
trials. J Urol 1998; 159: 433–436.
42 Lebret T, Herve JM, Gorny P, Worcel M, Botto H. Efficacy and
safety of a novel combination of L-arginine glutamate and
yohimbine hydrochloride: a new oral therapy for erectile
dysfunction. Eur Urol 2002; 41: 608–613.
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