Exposure of juvenile rats to the phytoestrogen daidzein impairs erectile function in a dose-related manner in adulthood

Health benefits of isoflavones such as genistein and daidzein have led to an increasing interest in consuming soybeans or soy-containing food. However, possible adverse effects of such plant estrogens on the male reproductive system, particularly penile erection, have not been sufficiently evaluated. In previous research, we observed that exposure of adult rats to daidzein could attenuate apomorphine-induced erections. To identify the impact of daidzein exposure in early life on erectile function, we evaluated erectile capacity using an apomorphine-induced erectile test and determining intracavernous pressure after exposure of juvenile rats to daidzein at a dose of 2, 20, or 100 mg/kg for 90 days. Meanwhile, the levels of sex hormones, including testosterone, luteinizing hormone, and follicle-stimulating hormone, were determined. Both subtypes of the estrogen receptor (alpha and beta) in the corpora cavernosa were also detected immunohistochemically. When the rats were examined at adulthood, we observed that those animals treated with a medium (20 mg/kg) or high (100 mg/kg) dose of daidzein, but not with a low dose (2 mg/kg), showed lower plasma testosterone levels and attenuated erectile parameters, including apomorphine-induced erections and intracavernous pressure concomitant with markedly decreased expression of estrogen receptor beta in the corpora cavernosa. However, the penis still grew to its normal size, as in controls. Thus, these results suggested that exposure of juvenile rats to daidzein in a relatively large amount could adversely affect penile erection in adulthood.     

Evaluation of efficacy of vitamin E and N-acetyl cysteine in gentamicin-induced nephrotoxicity in rats

Gentamicin (GM), an aminoglycoside, is widely employed in clinical practice for the treatment of serious gram-negative infections. The clinical utility of GM is limited by the frequent incidence of acute renal failure. This study was designed to investigate treatment and posttreatment renoprotective potential of vitamin E and N-acetyl cysteine (NAC) against GM-induced oxidative stress and renal dysfunction. Male Sprague-Dawley rats were divided into six groups: first group is the control group that received olive oil (0.1 mL/100 g B.W.), second is the one that was treated with GM (80 mg/kg/i.p./8 days), third is the one that was treated with GM (80 mg/kg/i.p./8 days) and vitamin E (50 mg/kg/i.p./8 days), fourth is the one that was treated with GM (80 mg/kg/i.p./8 days) and NAC (50 mg/kg/i.p./8 days), fifth is the one that was treated with GM (80 mg/kg/i.p./8 days), vitamin E (50 mg/kg/i.p./8 days), and NAC (50 mg/kg/i.p./8 days), and sixth is the one that was treated with GM initially for 8 days (at 80 mg/kg/i.p.) after which vitamin E (at 50 mg/kg/i.p.) and NAC (at 50 mg/kg/i.p.) were administered for 8 days. Serum creatinine, blood urea nitrogen, serum glucose, renal malondialdehyde, renal reduced glutathione, urine sodium, fractional excretion of sodium, and histopathological examination of kidney were performed after treatment. Gentamicin treatment caused nephrotoxicity as evidenced by marked elevation in serum creatinine, blood urea nitrogen, renal malondialdehyde, urine sodium, and fractional excretion of sodium. Study of renal morphology showed marked loss of epithelium in proximal convoluted tubule, inflammatory infiltrate in the form of lymphocytes, mainly in interstitium. Treatment and posttreatment with vitamin E and NAC significantly restored renal functions, reduced lipid peroxidation, enhanced reduced glutathione level, and restored the biochemical parameters. The results of this study demonstrate the therapeutic potential of vitamin E and NAC in gentamicin-induced nephrotoxicity.     

The effect of sildenafil on apomorphine-evoked increases in intracavernous pressure in the awake rat

PURPOSE: The aim of this study was to develop a quantitative, awake animal model to investigate the effect of sildenafil on centrally-evoked erectile activity. METHODS: Intracavernous pressures were recorded in awake, male Sprague Dawley rats after administration of apomorphine (100 or 250 microg./kg. subcutaneously). Sildenafil (100 microg./kg. intravenously) was then given 10 min. after a second dose of apomorphine. The time to first response, duration of response, and peak intracavernous pressure and area under the response, were measured before and after sildenafil. RESULTS: Apomorphine produced rhythmic increases in intracavernous pressure. The pressure increase consisted of two components. The amplitude of the first, tonic response was 58 +/- 3 mm. Hg, and a superimposed, burst-like increase in pressure elevated this further to 81 +/- 6 mm. Hg. Bilateral transection of the pudendal nerves abolished the burstlike pressure changes; bilateral transection of the cavernous nerves prevented both responses. The duration of the apomorphine-induced increase in intracavernous pressure was significantly (p = 0.003) prolonged by sildenafil (100 microg./kg.) from 37 +/- 4 to 62 +/- 11 s (n = 6). The overall intracavernous pressure response to apomorphine (100 microg./kg.), measured as the area under the curve, was significantly (p = 0.003) increased by sildenafil (100 microg./kg.) from 67 +/- 8 to 142 +/- 31 units (n = 6). N-nitro-L-arginine methyl ester (40 mg./kg. intravenously) prevented the apomorphine-induced responses. CONCLUSIONS: Monitoring intracavernous pressures in the awake rat represents a simple model to evaluate the effect of drugs on erectile function. Using this model we have shown that apomorphine elicits a rise in intracavernous pressure that can be prolonged by sildenafil. These results suggest that there may be a role for the combination of apomorphine and sildenafil in the management of erectile dysfunction.     

Intracavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients

A total of 100 men with organic impotence underwent a trial of intracavernous drug-induced erections with a mixture of papaverine (25 mg./ml.) and phentolamine (0.8 mg./ml.). The response rates, that is functional erections, were 100 per cent in patients with neurogenic impotence, 65.7 per cent in those with vasculogenic impotence, 90 per cent in the undetermined group and 64.7 per cent in the neurogenic/vascular impotence group. Of the responders 79.5 per cent elected to practice self-injection as a method to restore erectile function. The dose required to obtain functional erections in the purely neurogenic impotence group was significantly lower than that required in other groups. Complications were few and included 4 patients with sustained erections that required intervention. Intracavernous injection of vasoactive drugs appears to have promising value in the treatment and differential diagnosis of erectile dysfunction.     

Preliminary results with the nitric oxide donor linsidomine chlorhydrate in the treatment of human erectile dysfunction.

Recent experimental studies showed an important role of endothelium derived relaxing factor for cavernous smooth muscle relaxation. Since nitric oxide seems to account for the biological actions of endothelium derived relaxing factor, a study was done to examine a possible role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the treatment of erectile dysfunction. To determine a therapeutically useful dose 0.1, 0.2, 0.5 and 1 mg. SIN-1 were injected intracavernously in patients with erectile dysfunction. Each dose was given to 2 patients. Then, 63 patients received 1 mg. SIN-1, including 7 who had prolonged erections to minimal doses of papaverine plus phentolamine and 4 who did not respond with a full erection to other pharmacological agents. Intracavernous injection of SIN-1 induced a dose-dependent erectile response by increasing the arterial inflow and relaxing cavernous smooth muscles. Of the patients 29 had a full, 21 an almost full and 13 a moderate erection to 1 mg. SIN-1. There were no systemic or local side effects. In the patients with prolonged erections to papaverine plus phentolamine the mean duration of a full erectile response to SIN-1 was 57 minutes. Compared to the responses to a papaverine (15 mg./ml.) and phentolamine (0.5 mg./ml.) mixture, the erection induced by SIN-1 was superior in 10, comparable in 47 and inferior in 6 patients. Our data suggest a possible role for SIN-1 in the treatment of erectile dysfunction. Possible advantages may be that erection is induced by a mechanism similar to that occurring physiologically, a decreased risk of inducing prolonged erections and low therapy costs.     

The impact of alcohol ingestion on erections in rats as measured by a novel bio-assay

In rats, a syndrome of yawning and penile erection results from the administration of low doses of apomorphine, a dopamine receptor agonist shown to stimulate dopamine autoreceptors. Ethanol has been shown to influence dopamine metabolism. Low doses of ethyl alcohol (0.25 mg./kg.) failed significantly to alter apomorphine-induced yawning or penile erection, while 0.5 mg./kg. decreased erectile behavior but did not significantly alter the number of yawns. A reduction in both yawning and penile erection in response to apomorphine challenge was seen after the acute intraperitoneal injection of relatively high doses (1.0-3.0 mg./kg.) of ethanol. Two possible mechanisms of action may explain these phenomena. Alcohol may interfere with dopaminergic receptor mechanisms, or conversely, alcohol, through its actions on central dopamine metabolism may alter a second neurotransmitter/neuropeptide more directly responsible for the production of apomorphine-induced yawning and penile erection, possibly oxytocin.     

Cyclophosphamide-induced cystitis in freely-moving conscious rats: behavioral approach to a new model of visceral pain

PURPOSE: To develop a model of visceral pain in rats using a behavioral approach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic effects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis. MATERIALS AND METHODS: CP was administered at doses of 50, 100 and 200 mg./kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addition, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examination. Finally, to show that the bladder is essential for the CP-induced behavioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v. RESULTS: CP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specific postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pretreatment with naloxone. At the time of administration of morphine, histological modifications of the bladder wall, such as chorionic and muscle layer edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the same marked behavioral modifications as those observed in male rats. Administered at the dose of 20 mg. intravesically, CP did not produce any behavioral effects, whereas acrolein at 0.5 mg. intravesically induced behavioral modifications identical to those under CP 200 mg./kg. i.p., with the same maximal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavioral effects at all. CONCLUSIONS: Overall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.     

A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection

Experimental models to study the effect of agents on penile erection usually include electrical stimulation of peripheral nerves in anesthetized animals combined with systemic or intracavernous injection of drugs. The objective of this study was to demonstrate that conscious rabbits can be used as a simple and quantitative model for the assessment of compounds that show potential for the treatment of erectile dysfunction. Erection was assessed by measuring the length of uncovered penile mucosa before and after the intravenous (i.v.) administration of agents. Animals did not require anesthesia during the course of the study. The phosphodiesterase 5 (PDE5) inhibitors vardenafil x HCl (hereafter called vardenafil) and sildenafil were given intravenously, and measurements were taken for 0-5 h. The effects of phentolamine and milrinone were also evaluated. Vardenafil (0.1-3 mg/kg) induced dose-dependent penile erections in conscious rabbits following i.v. administration. The efficacy of vardenafil was potentiated, and the minimal effective dose was reduced significantly to 0.01 mg/kg by simultaneous administration of the nitric oxide (NO) donor sodium nitroprusside (SNP). Administration of the NO-synthase inhibitor L-NAME abolished the effect. Sildenafil was effective in this model after i.v. administration. The alpha-adrenergic receptor antagonist phentolamine (0.1, 0.3 and 1 mg/kg i.v.) induced erections with a slower t(max) compared with vardenafil and sildenafil. Intravenous administration of the PDE3 inhibitor milrinone (1 mg/kg i.v.) was less effective than the PDE5 inhibitor vardenafil. The conscious rabbit is a suitable and reliable model for the evaluation of compounds with potential for the treatment of erectile dysfunction. This was demonstrated using compounds that target different signaling pathways that induce smooth muscle relaxation in the penis.     

补肾助阳方对植物雌激素致勃起功能下降干预的实验研究

目的:研究补肾助阳方(养精胶囊)对大鼠阴茎勃起功能的影响机制。方法:成年雄性SD大鼠56只,随机分为7组,分别为空白对照组、大豆黄酮组、十一酸睾酮组、西地那非组及养精胶囊(高/中/低)剂量组。空白对照组给予生理盐水灌胃,其余各组100 mg/(kg·d)大豆黄酮灌胃30d。随后各实验组在给予大豆黄酮灌胃的同时,养精胶囊(高/中/低)剂量组分别给予1.26、0.63、0.315 mg/k/d剂量的养精胶囊组方,十一酸睾酮组给予4mg/(kg·d)剂量的十一酸睾酮,西地那非组给予2.5 mg/(kg·d)剂量的西地那非。分别在实验第0、30、60天观察各组大鼠阿扑吗啡诱导的自发勃起反应,记录勃起次数及勃起潜伏期,测定大鼠血清睾酮、黄体生成素水平,并观察大鼠阴茎海绵体组织切片。结果:实验第30天时,所有实验组大鼠阿扑吗啡诱导的勃起次数明显下降,勃起潜伏期延长,有统计学意义(P0.05)。第60天时,大豆黄酮组(1.39±0.42 vs 2.67±0.33)和大豆黄酮及低剂量养精胶囊组(1.33±0.49 vs 2.83±0.61)大鼠阿扑吗啡诱导的勃起次数明显下降(P0.05);阿扑吗啡诱导的大鼠勃起潜伏期只有大豆黄酮组[(16.33±3.11)min vs(8.50±0.93)min]和大豆黄酮及低剂量养精胶囊组[(15.50±3.21)min vs(8.63±1.54)min]明显延长(P0.05),其余各组变化不明显。实验第30天时,所有实验组大鼠血清睾酮、黄体生成素均有显著下降(P0.05)。实验第60d时,大豆黄酮组[(5.34±0.89)ng/ml vs(1.24±0.30)ng/ml]和大豆黄酮及低剂量养精胶囊组[(5.28±1.12)ng/ml vs(2.07±0.76)ng/ml]血清睾酮变化有统计学意义(P0.05)。两组的黄体生成素由(3.62±0.37)ng/ml、(3.79±0.28)ng/ml变为(2.09±0.12)ng/ml、(2.17±0.33)ng/ml,显著下降(P0.05)。切片结果显示对照组大鼠阴茎海绵体内海绵窦数目多,血管清晰可见。大豆黄酮加睾酮组、大豆黄酮加西地那非组和大豆黄酮加中、高剂量养精胶囊组大鼠海绵体与正常对照组相比,海绵窦数目减少。大豆黄酮组和大豆黄酮加低剂量养精胶囊组大鼠海绵体内海绵窦明显减少,血管少见。结论:使用高剂量养精胶囊治疗后,大鼠阴茎勃起功能恢复,对由植物雌激素引起的勃起功能下降有良好疗效。     

The characterization of a bio-assay of erectile function in a rat model

The investigation of biological phenomena in impotence using an animal system requires a determination of the erectile capabilities of the animal. Rats respond reliably to apomorphine by the exhibition of a phenomenon of erections and yawns. This property has been used to form the basis of a bio-assay of erectile integrity in the rat. We compared rats treated with placebo alone, sham operated rats, rats rendered surgically impotent and castrated rats with and without testosterone. Rats did not respond to placebo. The sham operated rats remained normal in all measured respects (2.66 erections/rat/30 minutes). Surgically impotent rats yawned normally but had no erections. Castrated rats did not have erections and had diminished yawning (3.21 yawns/rat/30 minutes vs. 7.7 for controls p less than .001) but responded normally after testosterone administration. The bio-assay is useful as a standard test of erectile function in the rat.     

The conditioned response erection (CRE)--a new approach to modelling erectile responses in the rat

Several animal models are currently used in erectile (dys)function research; these models fail to account for the conditions involving the more spontaneous erections in humans. Recently, we observed an increase in the number of 'spontaneously' occurring erections in rats with previous exposure to apomorphine (APO), a centrally acting drug that initiates penile erections and yawns. Based on this observation, we designed a series of experiments to characterize the development of enhanced, non-apomorphine-induced erections or 'spontaneous' erectile responses to vehicle administration in rats with previous exposure to APO. We further examined the effects of castration on these conditioned erections. Naive (ie never received APO) rats were administered vehicle (1 ml/kg saline) to determine the frequency of baseline erections and yawns. An alternating series of APO (80 microg/kg s.c.) and vehicle administrations were performed over several days and subsequent erectile and yawning responses were recorded. Following 3 sets of 3 APO administrations (with vehicle administered between sets), and the 3rd vehicle administration, these rats were then surgically castrated and allowed 30 days to recover. Following this, APO was administered 3 times to determine erectile and yawning responses post-castration, followed by vehicle administration to determine the effects of castration on conditioned APO responses. The major findings were: (1) that although naive rats had a basal spontaneous erectile response (0.75 +/- 0.88; 4 of 8 rats with at least one erection), repetitive administration (up to 22 treatments) of the central initiator apomorphine significantly increased the number of erections (1.8 +/- 0.7; 7 of 8 rats with at least one erection) and yawning (2.5 +/- 2.47) responses to vehicle administration; and (2) both spontaneous yawning and erectile responses were found to be androgen dependent since castration dramatically lowered the number of erections (0.13 +/- 0.35; 1 of 8 rats with at least one erection) and yawns (0). Therefore, this method of producing erections without a pharmacological manipulation provides an additional animal model which can be used in conjunction with the APO-induced erections in characterizing the physiology and pathophysiology of erectile function in conscious rats.     

Pro-erectile effect of systemic apomorphine: existence of a spinal site of action.

PURPOSE: Apomorphine exerts pro-erectile effects by acting on neurons in the paraventricular nucleus of the hypothalamus. In spinal cord injured rats we assessed whether apomorphine also directly activates the spinal autonomic and somatic neurons controlling penile erection MATERIALS AND METHODS: Intracavernous and blood pressure was monitored in groups of 10 anesthetized rats to quantify intracavernous pressure increases elicited after intravenous apomorphine. We determined the number and duration of increases, percent of maximum intracavernous pressure/mean diastolic blood pressure using the formula, maximum intracavernous pressure/diastolic blood pressure x 100, area under the intracavernous pressure curve/diastolic blood pressure and sum of the area under the curve/diastolic blood pressure. RESULTS: Of 2, 10, 50 and 250 microg./kg. intravenous apomorphine 50 microg./kg. induced significant pro-erectile effects and was subsequently used. In spinal cord injured rats 50 microg./kg. intravenous apomorphine significantly increased median maximum intracavernous pressure/diastolic blood pressure x 100 compared with vehicle injection (56 versus 27 seconds, p <0.001), area under the curve/diastolic blood pressure (21 versus 12 seconds, p = 0.07) and the sum of area under the curve/diastolic blood pressure (132 versus 32 seconds, p = 0.01). These pro-erectile effects of apomorphine were prevented by 50 mg./kg. hexamethonium intravenously or bilateral transection of the pelvic nerves. They were not affected by 3 mg./kg. of the peripheral D1/D2 antagonist domperidone intraperitoneally. In spinal cord injured rats subcutaneous pretreatment with 0.2 mg./kg. of the D1 antagonist SCH23390 significantly enhanced apomorphine induced erections, as indicated by an area under the curve/diastolic blood pressure of 23 to 30 seconds (p = 0.003), whereas they were not changed by 25 mg./kg. of the D2 antagonist sulpiride intraperitoneally. Under the same conditions 1 mg./kg. of the central D1/D2 antagonist haloperidol intraperitoneally only reduced the number of responding rats to 5 versus 10 of 10. CONCLUSIONS: In spinal cord injured rats systemic apomorphine elicits erection by acting at the spinal cord level. This finding suggests that systemic apomorphine elicits penile erections via spinal and supraspinal targets.     

Effect of testosterone on morphine withdrawal syndrome in rats

Aim： To determine whether testosterone is involved in morphine withdrawal syndrome （WS）. Methods： In order to induce dependency, rats were treated with subcutaneous injection of morphine （days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg）, and after the last dose of morphine （day 8） WS was induced by intraperitoneal injection of naloxone （1 mg/kg）. Wet dog shake （WDS）, abdomen writhing （AW）, and jumps （J） were recorded as indicators of WS. Results： The severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated （10 mg/kg/day for 8 days, i.p.） male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy （10 mg/kg/day for 8 days, i.m.） in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats. Conclusion： It can be concluded that testosterone might be effectively involved in morphine WS.     

Erectile dysfunction occurs following substantia nigra lesions in the rat

Erectile function was assessed 6 weeks following uni- and bilateral injections of 6-hydroxydopamine in the substantia nigra nucleus of the brain. Behavioral apomorphine-induced penile erections were reduced (5/8) and increased (3/8) in uni- and bilateral lesioned animals. Intracavernous pressures, following electrical stimulation of the cavernous nerve, decreased in lesioned animals. Lesions of the substantia nigra were confirmed by histology. Concentration of dopamine and its metabolites were decreased in the striatum of substantia nigra lesioned rats. Lesions of the substantia nigra are therefore associated with erectile dysfunction in rats and may serve as a model to study erectile dysfunction in Parkinson's disease.     

ORAL TRAZODONE IS NOT EFFECTIVE THERAPY FOR ERECTILE DYSFUNCTION: A DOUBLE-BLIND, PLACEBO CONTROLLED TRIAL

PURPOSE: The unusual side effect of priapism associated with the antidepressant trazodone has led researchers to evaluate its use for the treatment of erectile dysfunction. Previous studies have shown nearly 70% efficacy in patients. Unfortunately, these studies have been anecdotal, retrospective or of combination therapy with yohimbine. A placebo controlled, fixed dose, double-blind crossover study was performed to evaluate the safety and efficacy of oral trazodone for the treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 51 patients with at least 3 months of complete erectile dysfunction were randomized in a double-blind fashion to receive 50 mg. trazodone or placebo at bedtime. Evaluation consisted of a history, physical examination and laboratory studies, including hormonal evaluation, nocturnal penile tumescence evaluation, penile Doppler ultrasound and the Index of Sexual Satisfaction. Patients were followed at monthly intervals with an in clinic interview. After a 3-month treatment interval patients were reevaluated with index scores and crossed over after a 3-week washout period. Study end points included patient diary evaluations and index scores at the beginning of the study interval and the end of the first treatment period. RESULTS: Of the 51 patients who enrolled in the study 48 completed both phases. Mean patient age was 65 years (range 31 to 80). After the first 3-month treatment interval 19% of patients receiving trazodone had improved erections compared to 24% receiving placebo (p < 0.50). Of the trazodone group 35% had improvement in sex drive compared to 20% of the placebo group (p < 0.36). Mean Index of Sexual Satisfaction scores changed after treatment from 31.7 to 27.5 for the trazodone group (p < 0.50) and from 28.5 to 30.8 for the placebo group (p < 0.49). Side effects included drowsiness in 31% of the patients, dry mouth in 1% and fatigue in 19%. CONCLUSIONS: Trazodone is no more effective than placebo in improving erections and sexual function in patients with severe physiological erectile dysfunction.     

Alfuzosin improves penile erection triggered by apomorphine in spontaneous hypertensive rats

OBJECTIVES: Growing evidence suggest that BPH is a risk factor for ED. Since alfuzosin is a cornerstone in the treatment of BPH patients, we assessed the effect of alfuzosin on erectile function in rats when combined with a pro-erectile drug such as apomorphine. METHODS: Potencies of alfuzosin, apomorphine or the combination to relax norepinephrine (NE) precontracted corpus cavernosum tissue of spontaneous hypertensive rats (SHR) were determined. In anaesthetized rats, intracavernous and blood pressures were recorded after administration of apomorphine (10-250microg/kg s.c.) and alfuzosin (3-30microg/kg i.v.). RESULTS: Alfuzosin fully relaxed the NE-precontracted penile tissue (pIC(50)=6.62+/-0.7) while apomorphine, up to 10microM, did not produce any relaxation. The potency of alfuzosin to relax erectile tissue was not further enhanced with 10microM apomorphine. Apomorphine induced erections in rat while alfuzosin alone did not. However, alfuzosin (30microg/kg) significantly enhanced the potency of apomorphine, to induce erections (ED(50)=25microg/kg versus 57microg/kg). In addition, alfuzosin even at 3microg/kg, significantly increased the intracavernous pressure (ICP) during erectile events up to 52-55mmHg when compared to ICP values of 29mmHg with 50microg/kg apomorphine alone. CONCLUSION: These results show that alfuzosin enhances the number and amplitude of erections induced by apomorphine in SHR. Therefore, clinical evaluation of alfuzosin in association with apomorphine is warranted.     

乙醇对大鼠性功能影响的实验研究

目的:探讨乙醇对大鼠性功能的影响。方法:将60只Wistar雄性大鼠随机分为对照组、10%乙醇剂量组、20%乙醇剂量组、30%乙醇剂量组和40%乙醇剂量组,每组12只。分别以生理盐水、10%、20%、30%、40%食用乙醇各2ml给大鼠灌胃,每日1次。3个月后,观察各组大鼠性行为和药物诱发阴茎勃起的变化;用全自动化学发光分析仪测定各组大鼠血清睾酮的含量;以80μg/kg体重的阿朴吗啡大鼠颈部注射诱发阴茎勃起;用化学比色法测定阴茎平滑肌中一氧化氮合酶(NOS)的总量。结果:10%和20%乙醇剂量组大鼠药物诱发阴茎勃起的次数没有受到乙醇影响(P>0.05),但10%乙醇剂量组大鼠的乘骑和插入潜伏期延长,20%乙醇剂量组大鼠除了射精潜伏期外,其余性行为参数也受到抑制(P<0.05)。而30%乙醇剂量组与40%乙醇剂量组大鼠的性行为表现、药物诱发阴茎勃起实验均明显受到抑制(P<0.05)。与对照组相比,实验组血清睾酮含量和阴茎组织中NOS活性均减低(P<0.05)。结论:大鼠长期乙醇摄入后性功能障碍的发生与剂量有关。     

A rat model of Peyronie's disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression

PURPOSE: Our objective was to assess erectile function in saline-injected, transforming growth factor-beta 1 (TGF-beta1)-injected, and surgical injury rats after six weeks and to determine the role of nitric oxide in this rat model of Peyronie's disease. MATERIALS AND METHODS: Fifty-four adult male CD rats were divided into three groups: 1) saline-injected (0.1 ml.) into the tunica albuginea; 2) TGF-beta1 (0.5 microgram.) injected into the tunica albuginea; and 3) surgical injury to the tunica albuginea. All groups underwent electrical stimulation of the cavernosal nerve and pharmacological stimulation with acetylcholine, an endothelium-dependent vasodilator, after six weeks. In a separate group of animals, aminoguanidine (5 mg./kg. i.v.), a specific iNOS inhibitor, was administered and cavernosal nerve stimulation was performed. Cavernosal tissue was homogenized and constitutive and inducible NOS enzyme activity were measured by L-arginine to L-citrulline conversion in the presence and absence of calcium after 2 days, 3 and 6 weeks in all three groups. Cross-sections of the rat penises were examined using Hart and trichrome stains. RESULTS: Erectile function as measured by cavernosal nerve stimulation and acetylcholine injection was significantly lower (p <0.05) in the TGF-beta1-injected and surgical-injury rats when compared to the saline-injected rats. iNOS inhibition significantly increased (p <0.05) erectile responses to cavernosal nerve stimulation in the rat. iNOS was significantly higher (p <0.05) and constitutive NOS was downregulated (p <0.05) in the corpus cavernosum of the TGF-beta1-injected and surgical-injury rats after 6 weeks. The TGF-beta1-injected and surgical-injury rats exhibited thickening of the tunica albuginea, fragmentation of the elastic fibers, and collagen thickening around the neurovascular bundle. CONCLUSIONS: We have shown that erectile function is significantly lower in the TGF-beta1-injected and surgical-injury rats after 6 weeks at a time when iNOS is upregulated and constitutive NOS is downregulated. Furthermore, iNOS inhibition causes a greater erectile response in the rat, suggesting that iNOS may alter the vascular tone in the penis. These data document a possible mechanism by which some men with Peyronie's disease suffer from erectile dysfunction.     

Effect of a Chinese herbal medicine mixture on a rat model of hypercholesterolemic erectile dysfunction

PURPOSE: We examine the effect of a Chinese herbal medicine mixture on erectile function in a rat model of hypercholesterolemic erectile dysfunction. MATERIALS AND METHODS: In this study 32, 3-month-old Sprague-Dawley rats were used. The 8 control animals were fed a normal diet and the remaining 24 were fed 1% cholesterol diet for 4 months. After 2 months herbal medicine was added to the drinking water of the treatment group of 16 rats but not the cholesterol only group of 8. Of the 16 rats 8 received 25 mg./kg. per day (group 1) and 8 received 50 mg./kg. per day (group 2) of Chinese herbal medicine mixture. Serum cholesterol levels were measured at 2 and 4 months. At 4 months erectile function was evaluated with cavernous nerve electrostimulation in all animals. Penile tissues were collected for electron microscopy, and to perform Western blot for endothelial nitric oxide synthase, neuronal nitric oxide synthase, basic fibroblast growth factor (bFGF) and caveolin-1. RESULTS: Serum cholesterol levels were significantly higher in animals fed the 1% cholesterol diet compared to controls at 2 and 4 months. Nevertheless, there was no significant difference among group 1 (145 +/- 30 mg./dl.), group 2 (157 +/- 20) and the cholesterol only group (143 +/- 15). Systemic arterial pressure was not significantly different between the animals that were fed the 1% cholesterol diet and the controls. During electrostimulation of the cavernous nerve peak sustained intracavernous pressure was significantly lower in the cholesterol only group (50 +/- 23 cm. H2O) compared to the control group. Conversely erectile function was not impaired in the herbal medicine treated rats. Electron microscopy showed many caveolae with fingerlike processes in the cavernous smooth muscle and endothelial cell membranes in control and treated rats but not in the cholesterol only group of rats. Western blot did not show a difference among groups in protein expression for endothelial nitric oxide synthase and neuronal nitric oxide synthase in penile tissue but caveolin-1 and bFGF protein expression was significantly higher in groups 1 and 2 than in the cholesterol only and control groups. CONCLUSIONS: Rats developed erectile dysfunction after being fed a 1% cholesterol diet for 4 months. Although serum cholesterol levels were similar in the cholesterol only rats and those treated with Chinese herbal medicine mixture, erectile response was significantly better in the treated group. The mechanism of the herbal medicine is unknown. High levels of bFGF and caveolin-1 expression in the treated group may protect the cavernous smooth muscle and endothelial cells from the harmful effect of high serum cholesterol.     

雄激素对阿朴吗啡和电刺激诱导的去势大鼠勃起功能的影响

目的 :探讨应用安雄进行雄激素替代对去势大鼠勃起功能的影响。方法 :取40只成年雄性 SD大鼠 ,分为去势、高、低剂量安雄及假手术 4组。治疗 4周后采用阿朴吗啡 ( APO)皮下注射与电刺激海绵体神经诱导大鼠勃起 ,对其勃起功能进行评价。结果 :高、低剂量安雄组与假手术组大鼠 APO诱导的勃起成功率、勃起次数与电刺激诱导的海绵体内压 ( ICP)均较去势组大鼠为高或多 ,统计学处理差异有显著性 ( P<0 .0 1 )。结论 :通过 APO皮下注射和电刺激海绵体神经证实 ,去势导致大鼠勃起功能明显下降 ;采用安雄进行雄激素替代可恢复其勃起功能 ;去势既影响了药物诱发的勃起反应 ,也损伤了外周电刺激诱导的勃起反应