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。     

Metaraminol--an antidote in corpus cavernosum autoinjection therapy-induced prolonged erection

Up to now 65 patients with erectile dysfunction were treated by means of corpus cavernosum-autoinjection-therapy (CAT). The only side effect observed were 6 prolonged erections, which could successfully be treated in 3 cases by puncture and aspiration of the corpora cavernosa. In another 3 cases prolonged erection subsided after an intracavernous injection of 2 mg metaraminol. Erection induced by CAT was immediately interrupted by metaraminol in 10 other patients.     

Effects of an environmental anti-androgen on erectile function in an animal penile erection model

PURPOSE: Erectile function is testosterone dependent. For example, interference with either the levels or receptor binding of this steroid hormone may induce erectile dysfunction. Several environmental contaminants can interfere with the actions of endogenous hormones and have been termed 'endocrine disrupters.' p,p-DDE, a prominent and persistent metabolite of the insecticide DDT, has been shown to be an androgen receptor antagonist. The objective was to determine whether endocrine disrupters, as exemplified by p,p-DDE, are factors in the etiology of erectile dysfunction. MATERIALS AND METHODS: Using the established rat model of apomorphine-induced (80 microg./kg, s.c.) erections we assessed the dose-response effects of p,p-DDE in comparison to the known androgen receptor antagonist flutamide in acute (0.5 to 12 hours) and short-term (up to 8 weeks) experiments in both intact (Study 1) and castrated (Study 2) rats. As a follow up (Study 3), castrated rats treated with p,p-DDE were given increasing doses of testosterone (0.48 to 2.4 mg./kg., i.p.), eight weeks after p,p-DDE administration, to assess reversibility of p,p-DDE effect. RESULTS: A single dose of flutamide (50 mg./kg., i.p.) was found to significantly decrease apomorphine-induced erections to less than 50% over 12 hours following flutamide administration with recovery of erectile response within 48 hours. In comparison, a single dose of p,p-DDE (500 mg./kg., i.p.) decreased apomorphine-induced erections for at least two weeks (1.15+/-0.3 versus 2.5+/-1.1). Castration significantly decreased apomorphine-induced erections to approximately 0.5 erections/30 minutes. Flutamide (50 mg./kg.; i.p.) or p,p-DDE (50 mg./kg.; i.p.) did not further suppress the apomorphine erections in castrated rats. Testosterone supplementation (480 microg./kg; s.c.) in vehicle treated castrated rats recovered erectile response to pre-castrated levels, whereas p,p-DDE treated castrated rats required 4 times the dose of testosterone (2 mg./kg.; s.c.) given to vehicle treated rats to recover erections. CONCLUSIONS: The endocrine disrupter p,p-DDE can markedly interfere with erectile function and demonstrates persistence after a single dose. This supports our novel concept that environmental hormones may cause erectile dysfunction.     

电刺激阴茎背神经和海绵体内注射药物诱导大鼠阴茎海绵体内压反应

目的:评价阴茎海绵体内压(ICP)监测在电刺激阴茎背神经和海绵体内注射罂粟碱诱导大鼠阴茎勃起反应中的应用。方法:选取性成熟雄性SD大鼠8只,20%氨基甲酸己酯(1000mg/kg)腹腔注射麻醉下,暴露阴茎并解剖阴茎背神经(DN),将充满肝素盐水并连接于压力传感器的25G针头插入一侧海绵体,取另一30G头皮针插入对侧海绵体,分别用于测定ICP和注射血管活性药物。分别以电刺激海绵体神经(刺激参数:电压4V,波幅0.5ms,频率16Hz,持续20s)和海绵体内注射罂粟碱(0.4mg)诱发阴茎勃起,采用SMUPPC型生物信号处理系统记录ICP变化。结果:麻醉大鼠的ICP基线水平为(12.3±3.1)mmHg(1mmHg=0.133kPa),DN电刺激后约30～60sICP明显升高[(36.4±2.3)mmHg,P<0.05],电刺激结束后缓慢下降至基线水平。海绵体内注射罂粟碱后5～8min可诱发ICP明显升高[(28.4±6.1)mmHg,P<0.05]。结论:监测电刺激大鼠DN及海绵体内药物注射诱发的ICP,为阴茎勃起这一复杂神经血管活动的动物模型在体实验研究提供了一种客观准确的科学工具,对于进一步研究阴茎勃起生理和勃起功能障碍的发病机制,评价治疗勃起功能障碍新疗法的疗效等具有重要意义。     

Smooth muscle pathology and erectile dysfunction

Penile erection is a vascular phenomenon that results from smooth muscle relaxation, arterial dilation and venous restriction. The atherosclerosis of the penis that occurs with aging causes a decrease in penile oxygen tension. A reduction of smooth muscle cells has been demonstrated in relation with this change in oxygen tension. Changes in the ratio of penile collagen have also been observed and could explain the decrease in penile elasticity and compliance. Chronic ischemia is, therefore, associated with fibrosis but also with nitric oxide (NO)-cyclic guanosine monophosphate. The sensitivity of the alpha-adrenoceptors on the smooth muscle cells increases with aging. All those modifications can explain the prevalence of erectile dysfunction with aging. Low oxygen tension in prostanoid production may also play a role in the mechanism of ischemia-induced cavernosal fibrosis; however, intracavernous injections of prostaglandin E(1) do not seem to modify the intracavernous structures by reducing muscular atrophy. The effects of androgen on libido and sexual behavior are well established, but their role in the human erectile mechanism remains unclear. Several studies performed on animals have demonstrated impacts directly on both the physiological function and the trabecular structure of the corpora cavernosa in rats, dogs and rabbits. However, in humans, no study seems to demonstrate a role of testosterone on muscular atrophy or penile neurologic control. Testosterone treatment alters the human behavior but not penile physiologic processes. Further studies are necessary to explain the real role of testosterone not only on the peripheral mechanism of erection but also on the central control.     

Erectile impotence and its management

The use of pharmacologically-induced penile erections is a most promising mode of diagnosis and treatment of erectile impotence. A combination of papaverine and phentolamine is injected into the corpora cavernosa and the resultant erection usually lasts 2-4 hours. Insertion of penile prosthesis is expensive with a significant number of complications; whilst penile arterial revascularisation needs to be used very selectively for even moderately successful results to be achieved. Self-injection of the drugs can be taught and this technique appears to be an extremely safe and useful form of treatment for the majority of men with erectile impotence.     

Initial experiences with prostaglandin E1 and PGE1 prepared injections]

Between April and August 1989 we treated 50 patients with an erectile dysfunction. 23 patients (46%) had an organic, 17 (34%) a psychogenic and 7 patients (14%) a mixed origin of their impotence. In 3 patients the diagnosis has yet to be made. To induce pharmacological erections we used 20 micrograms of prostaglandin-E1 in a ready to use syringe. 64% (32 patients) achieved a full erection. Of the 18 patients insufficiently responding, 12 (67%) had an organic (in 11 patients vascular), 4 a psychogenic and 1 patient a mixed erectile dysfunction. In one patient the diagnosis has not been established at present. 14% (7) of the patients complained to have painful erections disturbing intercourse. The mean erection time was 2.5 hours (range 0.5-5.5). In one patient the intracavernous injection of prostaglandin-E1 resulted in a prolonged erection of more than seven hours, which was successfully treated by aspiration of blood from the corpora cavernosa and intracavernous injection of phenylephrine-hydrochloride. Nevertheless prostaglandin-E1 appears to be more physiological and to have less side-effects than papaverin-chloride.     

Long-term experiences with autoinjection therapy of papaverine in erectile dysfunction

Long-term experience with intracavernous self-injection of papaverine in 36 patients with erectile failure is reported. The average required dose of papaverine in 2037 documented injections was 31.5 mg. The rate of complications was low with a mean follow-up of 6.9 months. Prolonged erections occurred four times. Two patients reported the development of tolerance. In one man circumscribed induration of the tunica albuginea was observed, which disappeared spontaneously after change of the injection site. No infections of the corpora cavernosa, circulatory disturbances or signs of hepatotoxicity were observed.     

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.     

Delayed testosterone replacement restores nitric oxide synthase-containing nerve fibres and the erectile response in rat penis

OBJECTIVE: To elucidate the effect of testosterone on penile innervation. Materials and methods Three groups of six rats each were assessed; two groups (1 and 2) were castrated and the third (group 3) underwent a sham operation (control). Eight weeks after castration, group 2 received a subcutaneous injection with testosterone. At 8 weeks, the rats in group 1 and 3 underwent a final functional analysis while those in group 2 did so at 12 weeks. The evaluation included a subcutaneous injection with apomorphine to study centrally mediated erection, and cavernosal nerve electrostimulation and papaverine injection to study peripherally mediated erection. At death a penile mid-shaft specimen was taken for NADPH-diaphorase staining. RESULTS: In the apomorphine study, castration resulted in significantly fewer yawns and erections than in the control, and those in group 2 significantly better central erectile function than in the controls. The mean (SEM) number of nitric oxide synthase (NOS)-containing nerve fibres in the corpora cavernosa and both dorsal nerves of castrated rats, at 46.2 (9.1) and 203 (32.1), respectively, were significantly lower than in rats in group 2, at 84.1 (11.2) and 300.6 (17.1), and than in the controls, at 88.6 (10.9) and 306.3 (22.9), respectively. The intracavernosal pressure decreased significantly in the absence of testosterone, both after electrostimulation and intracavernosal papaverine injection. However, there was no difference between the control and group 2 rats in either the number of NOS-containing nerve fibres or in the peripheral erectile functional study. CONCLUSIONS: Testosterone acts on the nervous system to mediate erection; when it is absent there may be down-regulation of both the production and activity of NO, thereby decreasing the response to peripheral stimulation via the NO pathway. The restoration of erectile function seen in rats in group 2 supports this phenomenon. Delayed testosterone replacement has no detrimental effect on the restoration of the erectile mechanism after castration.     

The hemodynamics of erection at the level of the penis and its local deterioration

We have studied penile structure in 300 specimens from cadavers, 3,000 patients undergoing general physical examination and more than 700 patients operated on for organic impotence. Special attention has been focused on the closure mechanism of the corpora cavernosa during erection. Venous outlets of the corpora cavernosa normally are situated only on the distal third of the ventral penile surface. A firm, lasting erection requires a tight albuginea of the corpora cavernosa, with perfect closure of the venous outlets. During life use of the penis or, eventually, misuse by repeated long-lasting, firm erections (high pressure in the corpora cavernosa) results in deterioration of the tightness of the albuginea, especially when the albuginea is thin (25 per cent of the cases). We have found that a leakage factor of the corpora cavernosa is the most frequent cause of organic impotence in aging men.     

可分泌表达人降钙素基因相关肽重组腺相关病毒对糖尿病大鼠阴茎勃起的作用

目的:探讨重组腺相关病毒(rAAV)介导人降钙素基因相关肽(hCGRP)基因转移在糖尿病大鼠阴茎海绵体平滑肌分泌表达及其对阴茎勃起的作用。方法:建立链佐脲菌素(STZ)糖尿病大鼠模型,随机分为3组,分别将VssHGCMV-hCGRP、VssCMV-GFP和rAAV空病毒液注射于阴茎海绵体。在注射后5 d,采用SMUP-PC型生物信号处理系统检测阴茎背神经电刺激诱发的阴茎勃起反应及海绵体内压(ICP)变化。切取海绵体组织,通过免疫组化技术和激光共聚焦显微镜分别检测hCGRP和绿色荧光蛋白(GFP)表达,以放射免疫法检测组织中环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)变化。结果:在VssCMV-GFP转染后5 d,显示阴茎海绵体内几乎所有组织均有广泛的GFP表达,而rAAV空病毒转染的海绵体则无GFP表达。VssHGCMV-hCGRP转染STZ诱导的糖尿病大鼠后5d,电刺激阴茎背神经可诱发明显的阴茎勃起,监测ICP明显增高[(60.5±4.5)mm Hg,1 mm Hg=0.133kPa],而对rAAV空病毒转染的对照组STZ糖尿病大鼠以同样的参数电刺激阴茎背神经则无勃起反应,ICP无明显增加[(22.3±1.3)mm Hg],两组差异有显著性(P<0.01)。免疫组化观察显示在VssHGCMV-hCGRP转染的STZ糖尿病大鼠阴茎海绵体组织中hCGRP表达增强,同时当电刺激阴茎背神经诱发勃起反应时,海绵体内cAMP和cGMP水平均升高,分别为(48.4±6.5)nmol/L和(21.2±13.6)nmol/L,较rAAV空病毒组[(16.7±2.5)nmol/L和(0.42±0.12)nmol/L]明显增高(P<0.01)。结论:经阴茎海绵体内注射重组腺相关病毒VssHGCMV-hCGRP在糖尿病大鼠阴茎海绵体内获得了hCGRP转基因高效表达,其可增加阴茎背神经电刺激诱发的阴茎ICP和勃起反应。     

Relationship between perineal muscle contractions, penile tumescence, and penile rigidity during nocturnal erections

The mechanism of penile erection and erectile dysfunction is still unclear and widely debated. The role of the perineal muscles in the erectile process, especially in changes in intracavernous pressure, is increasingly being studied on the hypothesis that perineal muscular contractions are essential to full penile rigidity. In a previous investigation we studied the correlation between voluntary perineal muscle contractions and intracavernous pressure during artificially induced erections. The purpose of the current study was to examine whether under normal conditions of nocturnal erection a similar relationship exists between the electromyographic activities of perineal muscles and changes in penile rigidity. Nocturnal penile recordings were made of seven volunteers with psychogenic erectile dysfunctions. During nocturnal erections simultaneous computerized recordings were made of penile tumescence, penile rigidity, and electromyographic activities of perineal muscles. The peaks for the three variables were reached simultaneously. The results of this study suggest the existence of two different physiologic phases: a vascular phase and a muscular phase. Furthermore, in cases of dysfunctions, specific diagnostic assessment and therapeutic management will be required for both penile tumescence and penile rigidity.     

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.     

Atorvastatin but not elocalcitol increases sildenafil responsiveness in spontaneously hypertensive rats by regulating the RhoA/ROCK pathway

Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil-containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose-dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, alpha-smooth muscle actin, SM22alpha, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR, likely by interfering with RhoA/ROCK signaling within the penis.     

Functional evaluation of penile hemodynamics

A multidisciplinary study was performed on 200 consecutive patients with erectile dysfunction more than 1 year in duration, which included a standardized intracavernous injection of a vasoactive substance mixture (15 mg. per ml. papaverine plus 0.5 mg. per ml. phentolamine). The multidisciplinary findings correlated well with the intracavernous dose needed for full erection. The group without pathological hemodynamic findings (36 patients) needed an average of 0.67 ml. and the group with pathological inflow (107) needed an average of 1.07 ml. In the venous insufficiency group (57 patients) only 18 achieved full erections with an average of 2.1 ml. (39 achieved tumescence only to 3 ml.). The results show that standardized intracavernous injection of a vasoactive substance mixture is a useful method to evaluate penile hemodynamics. This pharmacological test appears to be effective in the differential diagnosis of nonvascular and vascular erectile dysfunction.     

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.     

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.     

Induction of an erection using papaverine

In 61 patients erectile impotency was treated with papaverine injections into penile spongy body: initially 20-30 mg/day, then followed several days of intermittence, and then the dosages were built up with regard to the optimum time of erection for each person. Dosages higher than 80-100 mg were not advisable because of the evidence of prolonged erections. Recorded in 6 patients (7 times) prolonged erections lasted from 5 to 16 hrs (in 5 cases it was stopped by intracavernous injection of dopamine but in 2 patients cavernotomy was performed). A total of 300 sessions of papaverine intracavernous injections were made in 61 patients before the copulation (out of them 16 patients injected the drug themselves). During the treatment the patients were warned against prolonged erections: when it lasted for more than 4 hrs emergency clinical treatment be required for priapism prevention. It was proved that an adequate dosage of papaverine autoinjections into a spongy body was a simple, safe and effective method to cure erectile impotency, especially in patients with nonadvanced psychoneurological or vasculogenic disorders.     

Maintenance of erection of penile glans, but not penile body, after transection of rat cavernous nerves

Two experiments tested the widely held assumption that the cavernous nerves (CN) are essential not only to erection of the penile body, via the corpora cavernosa, but also to erection of the glans penis, via the corpus spongiosum. In Experiment 1, the copulatory behavior and reflexive erections of male rats were studied before and after the CN were transected bilaterally (n = 8), unilaterally (n = 6), or sham-operated (n = 6). In postoperative tests, bilaterally operated males were severely impaired in their attempts to effect intromission, and they had the expected deficits in reflexive erections of the penile body, but their capacity for erection of the glans penis was only minimally impaired. Sham-operated males were unaffected by surgery, and unilaterally transected males had intermediate values. Experiment 2 tested the hypothesis that activity of the bulbospongiosus muscles was responsible for the residual erectile capacity of the glans after CN transection in Experiment 1. Males had bilateral sections of the CN (n = 9), or of the nerves innervating the bulbospongiosus muscles (n = 10), or of both of these nerves (n = 8), or sham surgery (n = 10). Relative to CN transection alone, the combined denervation further reduced glans penis erections, but did not eliminate them. These results suggest that the cavernous nerves of the rat are not the only peripheral nerves facilitating vascular engorgement of the corpus spongiosum.