Yohimbine enhances the effect of sildenafil on erectile process in rats

Abstract

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 10 μmol kg−1. Yohimbine alone failed to potentiate erectile responses but yohimbine (1 μmol kg−1) significantly potentiated the effect of sildenafil 1–10 μmol kg−1 and 1 mmol kg−1, 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 sildenafil-induced 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.

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 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 α2-adrenergic receptors.5, 6, 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, 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 kg−1), 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 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 90° 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

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 μg kg−1 estradiol benzoate followed by 1 mg kg−1 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. 1)

    mount latency (ML): the time from introduction of the female to the occurrence of the first mount;

  2. 2)

    intromission latency (IL): the time from introduction of the female to the occurrence of the first intromission;

  3. 3)

    ejaculation latency (EL): time from the first intromission to ejaculation;

  4. 4)

    PEI: time from ejaculation to the subsequent intromission;

  5. 5)

    intromission frequency (IF): number of intromissions preceding ejaculation;

  6. 6)

    ejaculation frequency (EF): number of ejaculation in a session; and

  7. 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.

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 10 μmol kg−1. Electrical stimulation of the CN produced an ICP/SAP value of 0.413±0.075 mm Hg in the presence of 1 mmol kg−1 sildenafil compared with 0.095±0.016 mm Hg in its absence 1 min after i.v. injection, n=8 (Figure 2).

Figure 1
figure1

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.

Figure 2
figure2

Effect of i.v. sildenafil (1 μmol kg−1 to 1 mmol kg−1) 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 P<0.05. ICP, intracavernosal pressure; i.v., intravenous; SAP, systemic arterial pressure.

Effect of yohimbine on nerve-stimulated erectile responses

Yohimbine (0.1 μmol kg−1 to 1 mmol kg−1) failed to increase ICP/SAP significantly compared to control values, neither at 1 min nor at 5 min after i.v. injection, n=7 (Figure 3).

Figure 3
figure3

Effect of i.v. yohimbine (0.1 μmol kg−1 to 1 mmol kg−1) 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.

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 μmol kg-1 with increasing doses of sildenafil (1 μmol kg−1 to 1 mmol kg−1). The effect of all combinations tested was significantly greater than the effect of yohimbine alone. One minute after i.v. administration, percentage potentiation of ICP/SAP induced by a combination of 10 μmol kg−1 sildenafil and 1 μmol kg−1 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 kg−1 sildenafil and 1 μmol kg−1 yohimbine) 5 min after injection, n=7 (Figure 4).

Figure 4
figure4

Effect of sildenafil (1 μmol kg−1 to 1 mmol kg−1), yohimbine (1 μmol kg−1) 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 P<0.05, #denotes significant difference compared to yohimbine group at the level of P<0.05 and *denotes significant difference compared to the sum of individual effects at the level of P<0.05. ICP, intracavernosal pressure; SAP, systemic arterial pressure.

Effect of sildenafil, yohimbine and sildenafil/yohimbine combination on mating behavioral parameters

Intraperitoneal injection of yohimbine (1 μmol kg−1), n=8 in male rats increased sexual motivation parameters. It significantly reduced ML, EL, PEI and ICI compared to control values. Sildenafil (10 μmol kg−1, n=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 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 μmol kg−1 yohimbine+10 μmol kg−1 sildenafil, n=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, 6 and 7).

Figure 5
figure5

Effect of yohimbine (1 μmol kg−1) 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 P<0.05.

Figure 6
figure6

Effect of sildenafil (10 μmol kg−1) 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 P<0.05.

Figure 7
figure7

Comparison of the effect of sildenafil (10 μmol kg−1), yohimbine (1 μmol kg−1) 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 P<0.05, #denotes significant difference compared to the yohimbine group at the level of P<0.05 and *denotes significant difference compared to the sum of individual effects at the level of P<0.05.

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).

Table 1 Effect of sildenafil, yohimbine and sildenafil/yohimbine combination on SAP

Discussion

In the in vivo rat model where erection is induced by electrical stimulation of the CN, i.v. administration of sildenafil (10 μmol kg−1 to 1 mmol kg−1) 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 anesthetized 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 injected intraperitoneally, it reduced mount, intromission and ELs and ICI, indicating an increase in arousal and motivation. The combination potently 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 kg−1) 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, 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 α1- and α2-adrenergic receptor antagonist. It seems from the latter study that α1-receptors antagonism predominates at high doses since yohimbine (1 × 10−8 and 1 × 10−7 M) enhanced electrically induced contractions in isolated corpus cavernosum while 1 × 10−6 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 α2-receptors attenuating contraction mediated by norepinephrine (NE); (2) inhibition of pre-junctional α2-receptors on the adrenergic nerves resulting in an increase in the release of NE and (3) inhibition of the binding to pre-junctional α2-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, 30, 31 It is reported that yohimbine facilitates sexual arousal by acting on α2-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-dose-dependent 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.

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.

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Correspondence to T Mostafa.

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Senbel, A., Mostafa, T. Yohimbine enhances the effect of sildenafil on erectile process in rats. Int J Impot Res 20, 409–417 (2008). https://doi.org/10.1038/sj.ijir.3901630

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Keywords

  • erectile dysfunction
  • sildenafil
  • yohimbine
  • phosphodiesterase inhibitor
  • corpus cavernosum

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