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Yohimbine Enhances the Effect of Sildenafil on Erectile Process in Rats

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Yohimbine Enhances the Effect of Sildenafil on Erectile Process in Rats International Journal of Impotence Research (2008) 20, 409–417 & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00 www.nature.com/ijir ORIGINAL ARTICLE Yohimbine enhances the effect of sildenafil on erectile process in rats AM Senbel1 and T Mostafa2 1Pharmacology 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 kgÀ1. Yohimbine alone failed to potentiate erectile responses but yohimbine (1 lmol kgÀ1) significantly potentiated the effect of sildenafil 1–10 lmol kgÀ1 and 1 mmol kgÀ1, 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. 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 agents, including the PDE5 inhibitors, phentola- 1,2 mine, yohimbine, L-arginine and so on. Sexual behavior and erectile function are influenced Introduction of sildenafil citrate (Viagra Pfizer by emotional and cognitive functions. At the central Inc., New York, NY, USA) in 1998, has been an nervous system level hypothalamic and limbic advancement in improving erectile function and systems are responsible for central erectogenic enabling successful sexual intercourse in men with signals facilitating spinal cord pathways, which broad spectrum ED.3,4 Yohimbine is an indole lead to erection via peripheral autonomic nerves.1 alkaloid whose aphrodisiac activity may be Current strategies for the pharmacological treatment mediated through a combination of central nervous of erectile dysfunction (ED) favor the use of oral system effects and peripheral effects including blockade of pre- and postsynaptic a2-adrenergic receptors.5–7 Placebo-controlled studies have sug- gested the effectiveness of yohimbine in treating ED Correspondence: Professor Dr T Mostafa, Andrology and due to psychogenic or mild organic etiology, but the Sexology Department, Faculty of Medicine, Cairo Uni- 8 versity, Cairo 11562, Egypt. outcome of its use was, however, disappointing. E-mail: [email protected] Since the advent of sildenafil, there has been a Received 27 December 2006; revised 28 September 2007; resurgence of interest in ED and an increase in 9 accepted 25 October 2007; published online 17 April 2008 patients presenting with this disease. However, Combined effect of yohimbine and sildenafil AM Senbel and T Mostafa 410 several studies showed that administering sildenafil computed at the maximal effect after CN stimulation could not result in rigidity sufficient for satisfactory and SAP is the systemic arterial pressure computed sexual intercourse in 11–22% of patients with at the same time) was calculated. ICP/SAP 1 and psychogenic and 36–65% with organic ED.10,11 5 min after intravenous (i.v.) administration of the Combination drug therapy seems appealing to treat drug were compared to control cavernous responses patients with ED in whom monotherapy with in the same rat. Percentage potentiation in ICP sildenafil failed. Therefore, combining the centrally induced by the combinations was then statistically acting drug yohimbine with the peripheral condi- compared to that induced by every drug alone in the tioner sildenafil might be an attractive approach. previous set of experiments at the same time This study therefore was designed to investigate the interval. In this set of experiments, the drug(s) and effect of yohimbine on sildenafil-induced facilita- drug combinations were administered i.v.; the effect tion of centrally and peripherally mediated erectile was recorded 1 and 5 min after injection. A catheter process in male rats. 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 Materials and methods original experiment. Animals Experiments were carried out on male albino rats Intravascular cannulation and measurement of 200–350 g weight (approximately aged 4–6 months) blood pressure and female albino rats 150–200 g. All animals used Measurement of blood pressure and heart rate in rats were bred in the animal house at the Faculty of was made as described previously by Tseng et al.14 Pharmacy according to NIH guidelines, housed About 1 cm incision was made in the skin of the under constant environmental conditions, fed diets groin and the underlying muscles were cut, then the consisting of wheat or bread soaked in milk. Water femoral artery and vein were exposed and freed was allowed ad libitum. 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 polyethyl- ene catheter, 20 cm length filled with heparinized Measurement of ICP in rats saline, was introduced. The arterial catheter Experiments have been conducted by measuring was connected to the pressure transducer and intracavernosal pressure (ICP) changes elicited arterial blood pressure was displayed on a Grass by electrical stimulation of the cavernosal polygraph. nerve (CN) in anesthetized rats according to the method described by Giuliani et al.12 Male rats were anesthetized by intraperitoneal injection of thiopen- tal (50 mg kgÀ1), then the skin overlying the penis Behavioral testing in rats was incised, and the prepuce was degloved to Copulatory behavioral tests on rats were performed expose the corpora cavernosa. A 26-gauge needle as described previously by Butcher et al.15 Male and filled with heparinized saline was carefully inserted female rats were housed at room temperature for 1 into the corpus cavernosum on one side to measure week before the start of the experimental period, ICP. The needle was sealed to a polyethylene 50 three or four to a cage. All experiments were tubing of 20 cm length filled with heparinized performed between 1100 and 1500 hours in a sound saline, connected to a Gould-Statham pressure attenuated room.16 Sexual activity of rats was transducer (Oxnard, CA, USA). ICP was displayed evaluated after four selection mating tests with on a Grass polygraph (Model 7D, Grass Inst. Co., receptive females. After selection tests, animals MA, USA). were admitted to the experimental session if they Through a lower suprapubic midline incision, the had exhibited at least one ejaculation per test.17 The lateral prostate was dissected and the major pelvic normal coital pattern in male rats is characterized by ganglion was identified. The CN was unilaterally the following behavioral sequence: (1) mounting freed from its facial attachments and stimulated of the female followed by a penile intromission electrically using a bipolar platinum electrode lasting approximately 1/3 s, (2) withdrawal of the placed 3–4 mm distal to the major pelvic ganglion.13 penis and dismount and (3) a brief rest interval of The two poles of the electrode were separated by about 40–60 s. This sequence is then repeated 2 mm and the electrode was connected to an several times until ejaculation occurs with the electronic stimulator (Letica, Panlab, Model 12106/ terminal intromission of the series. Ejaculation was 150, Spain). CN was stimulated for 1 min, the pulse identified by vigorous thrush and longer intro- parameters were 5 V, 1 ms duration and 0.5–10 Hz mission period, and was always followed by a frequency. Maximum rise in ICP during nerve resting period (post-ejaculatory interval (PEI)) of stimulation was measured. ICP/SAP ratio (ICP is 10–15 min.15 International Journal of Impotence Research Combined effect of yohimbine and sildenafil AM Senbel and T Mostafa 411 Estrous was induced in the stimulus female by level. Throughout the manuscript ‘n’ indicates the means of a combined treatment of estrogen and number of rats. progesterone. Forty-eight hours before testing, the females were subcutaneously injected with À1 À1 60 mgkg estradiol benzoate followed by 1 mg kg Results progesterone 4 h prior the observation period. After a 10-min adaptation period in the observation cage, Effect of sildenafil on nerve-stimulated erectile a receptive female was presented to the male by responses dropping it gently into the cage. By direct observa- This set of experiments began with 3–5 CN stimula- tion, the following behavioral parameters were tions at different frequencies to select a suitable recorded: frequency that produced a submaximal increase in (1) mount latency (ML): the time from introduction ICP.
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