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。     

Noncholinergic penile erection in mice lacking the gene for endothelial nitric oxide synthase.

With the current understanding that nitric oxide (NO) mediates penile erection, the endothelial isoform of NO synthase (eNOS) has been implicated in this function. We undertook this study applying transgenic mice with targeted deletion of the eNOS gene (eNOS-/- mice) as an experimental approach to evaluate the importance of eNOS in cholinergically stimulated erectile function in vivo. Combined pharmacostimulation with intracavernosal carbachol (3 ng) administration and submaximal cavernous nerve (CN) electrical stimulation (16 Hz, 5 millisecond, 1 V) simultaneous with intracavernosal pressure (ICP) monitoring, and both biochemical assay of NO synthase activity and Western blot analysis of eNOS protein content in penile tissue, were performed on eNOS-/- mice and wild-type controls. Combined intracavernosal carbachol administration and submaximal CN electrical stimulation raised the recorded ICP, elicited by CN electrical stimulation alone in wild-type mice (from 35.7 +/- 2.7 to 48.1 +/- 5.5 mm Hg, P < .05) but not in eNOS-/ - mice (from 54.9 +/- 6.3 to 51.0 +/- 9.5 mm Hg, not significant [NS]). Pretreatment with the nonselective nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 100 mg intracavernosally) blocked electrically stimulated ICP responses in eNOS-/- mice to baseline levels (37.8 +/- 4.4 vs 12.7 +/- 4.0 mm Hg, P < .05). In penes of eNOS-/- mice, approximately 60% NO synthase activity of wild-type penis levels was retained (NS), and eNOS protein was absent. We concluded that eNOS-/- mice preserve erectile function on the basis of a noncholinergic but NO-dependent mechanism and that eNOS physiologically mediates penile erection under cholinergic stimulation.     

Effect of intraurethral papaverine on penile erection in rats

OBJECTIVES: The aim of this study is to investigate erectile response to intraurethral administration of papaverine in rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were used in this study. Under urethane anesthesia, penis was exposed and intracavernous pressure (ICP) was recorded through a 23-gauge needle, which was inserted into right corpus cavernosum. Effects of intraurethral application of incremental doses of 0.2 ml papaverine gel (4-17.5 mg) on intracavernosal pressure were observed and compared with those of 0.4 mg papaverine applied into corpus cavernosum. Mean arterial blood pressure (MABP) and heart rate were also monitored. RESULTS: The mean basal ICP was 8.9 +/- 1.8 mm Hg. Intraurethral administration of papaverine did not increase ICP at any doses used in this study. After intracavernous injection of papaverine (0.4 mg), a significant increase in the ICP occurred from resting (8.9 +/- 1.8 mm Hg) to a peak at 57.5 +/- 9.9 mm Hg and persisted for 22.3 +/- 6.7 minutes (p < 0.05). The latter application significantly decreased MABP (22.3 +/- 3.1 mm Hg; p < 0.05). CONCLUSIONS: Intraurethral administration of papaverine does not seem to be an alternative to other erectile dysfunction treatment modalities. However, further studies on animals are necessary at higher concentrations or in combination with other mucosal enhancers to increase the effect of intraurethral administration of papaverine.     

衰老对大鼠阴茎海绵体内皮细胞功能的影响

目的 :探讨衰老对大鼠阴茎海绵体内皮细胞功能的影响。　方法 :利用YH 4压力传感器分别检测了青龄(5个月 )和老龄 (2 0个月 )两组大鼠阴茎海绵体内压 (ICP)在乙酰胆碱 (Ach)、硝普钠 (SNP)和A2 3187作用下的变化 ;并测定了两组大鼠阴茎海绵体一氧化氮合酶 (NOS)的活性。　结果 :青龄组基础ICP为 (9.4± 2 .3)mmHg(1mmHg=0 .133kPa) ,老龄组为 (7.2± 1.7)mmHg,二者间差异无显著性 (P >0 .0 5 )。在浓度分别为 10 -6、10 -5、10 -4mol/L的Ach作用下 ,两组大鼠ICP值间差异均有显著性 (P <0 .0 1)。当Ach浓度为 10 -4mol/L时 ,两组大鼠ICP值达到最高 ,青龄组为 (5 4 .8± 4 .2 )mmHg ,老龄组为 (40 .3± 2 .8)mmHg。A2 3187(10 μmol/L)可以进一步提高老龄组ICP值 ,由(40 .3± 2 .8)mmHg上升到 (5 6 .2± 4 .1)mmHg ,两者间差异有显著性 (P <0 .0 1) ;青龄组提高不明显 ,由 (5 4 .8± 4 .2 )mmHg上升到 (5 5 .8± 4 .7)mmHg ,两者间差异无显著性 (P >0 .0 5 )。在SNP(10 -4mol/L)作用下青龄组ICP值为(5 8.9± 4 .7)mmHg ,老龄组为 (5 1.7± 5 .3)mmHg ,两者间差异无统计学意义 (P >0 .0 5 )。两组大鼠阴茎海绵体内NOS的活性差异无统计学意义 (P >0 .0 5 )。　结论 :大鼠阴茎海绵体内皮细胞对内皮细胞激动剂     

DOPAMINERGIC NEUROTRANSMISSION AT THE PARAVENTRICULAR NUCLEUS OF HYPOTHALAMUS IN CENTRAL REGULATION OF PENILE ERECTION IN THE RAT

PURPOSE: To investigate whether the paraventricular nucleus of hypothalamus (PVN) is involved in the central regulation of apomorphine-induced penile erection in the rat, and to decipher dopamine receptor subtypes in the PVN that are involved in apomorphine-induced penile erection. MATERIALS AND METHODS: Male adult Sprague-Dawley rats (200 to 300 gm.) anesthetized with pentobarbital sodium were used. The intracavernous pressure (ICP), recorded along with systemic and mean arterial pressure (SAP, MAP) as well as heart rate (HR), was measured via a 26-gauge needle inserted into one corpus cavernosum. The PVN was activated by stereotaxically delivered apomorphine hydrochloride (0.1 nmol./100 nl.). Injection of saline into PVN served as a vehicle control. To investigate the participation of dopamine receptor subtypes in the PVN on apomorphine-induced penile erection, D1 or D2 receptor antagonist, SCH-23390 (100 pmol./100 nl.) or sulpiride (100 pmol./100 nl.) respectively, was administered into the PVN prior to subcutaneous application of apomorphine (80 microg./kg.). The effects on ICP of microinjection of D1, D2 or D3 receptor agonist, SKF-38393 (200 pmol./100 nl.), lisuride (200 pmol./100 nl.) or 7-hydroxy-DPAT (200 pmol./100 nl.) respectively, into the PVN were also evaluated. RESULTS: The mean resting ICP was 5.2+/-0.4 mm. Hg. Upon administration of apomorphine into the PVN, there was a significant increase in ICP that peaked at 50.7+/-5.3 mm. Hg and persisted for 45.2+/-18.0 minutes after an onset latency of 677.7+/-311.6 seconds. Yawning and teeth gnashing were also observed in most of animals during the period of ICP increase. There was no significant change in SAP, MAP or HR. In addition, there was no elevation in ICP after administration of saline to the PVN or direct injection of apomorphine into the cavernous tissue. Microinjection of D1 or D2 receptor antagonist into the PVN blocked the increase in ICP after subcutaneous administration ofapomorphine. Direct application of D2, but not D1 or D3 receptor agonist into the PVN, on the other hand, increased the ICP. CONCLUSIONS: Our results demonstrate that application of apomorphine to the paraventricular nucleus of hypothalamus elicited penile erection in the rat. Such an increase in ICP to apomorphine was due mainly to activation of the D2 receptor subtype in the PVN. These observations indicate that PVN may be involved in the central regulation of apomorphine-induced penile erection in the rat.     

阴茎海绵体内注射川芎嗪对兔阴茎勃起效应的影响

目的 观察阴茎海绵体内注射川芎嗪对兔阴茎勃起效应的影响.方法 12只成年雄性新西兰大白兔,静脉麻醉后游离一侧颈总动脉和阴茎海绵体,颈总动脉插管与电生理记录仪连接监测平均动脉压(MBp),阴茎海绵体内置入25 G针头与电生理记录仪连接用于测定阴茎海绵体内压(ICP).通过在兔阴茎海绵体内注射不同剂量(0.5～5.0 mg/kg)川芎嗪和等体积生理盐水,分别记录ICP变化(ICP)、阴茎膨胀持续时间(DT)和MBp的变化.结果 阴茎海绵体内分别注射不同剂量的川芎嗪(0.5、1.0、2.0、5.0 mg/kg),ICP分别由基线增加至(19.1±3.7)、(24.8±2.1)、(30.2±4.8)、(39.7±6.1)mm Hg(1 mm Hg=0.133 kPa), ICP为6.5～25.8 mm Hg,最大ICP为(25.8±5.9)mm Hg,DT为(8.5±2.8)～(22.9±7.3)min.阴茎海绵体内注射川芎嗪呈剂最依赖性提高ICP(P<0.05),对MBp没有显著影响(P>0.05).结论 川芎嗪呈剂量-效应依赖性地增强兔阴茎勃起效应.     

Involvement of L-arginine/nitric oxide pathway at the paraventricular nucleus of hypothalamus in central neural regulation of penile erection in the rat

The objective of this study is to investigate whether the L-arginine/nitric oxide pathway is involved in the neurotransmission of paraventricular nucleus of hypothalamus (PVN) activation-induced penile erection in the rat. Male adult Sprague-Dawley rats anesthetized with pentobarbital were used. The femoral artery was cannulated to measure systemic and mean arterial pressure (SAP and MAP), and heart rate (HR). A 26-gauge needle was inserted into corpus cavernosum to measure the intracavernous pressure (ICP) simultaneously with SAP, MAP and HR on a polygraph. Four groups of study were arranged: (1) stereotaxically delivery of L-arginine (500 nmol/500 nl) into PVN; (2) administration of a mixture (1 microl) containing N(G)-Nitro-L-arginine methyl ester (L-NAME) 500 nmol and L-arginine 500 nmol into PVN; (3) microinjection of saline 500 nl into PVN as a vehicle control; and (4) intracavernous injection of L-arginine (100 nmol/50 microl). The ICP, SAP, MAP and HR were monitored for at least 2 h after each administration of the experimental agents. Upon administration of L-arginine into PVN, there was a significant increase of ICP from resting 9.6+/-2.5 mmHg to peaked at 64.4+/-9.8 mmHg after a latency of 3016.0+/-1749.7 s and with a duration of 27.6+/-15.8 min. There was no change of resting ICP after administration of the mixture of L-NAME and L-arginine into PVN. Application of saline to PVN and intracavernous injection of L-arginine failed to increase ICP. Based on elicitation of penile erection upon administration of L-arginine into PVN, and elimination of this L-arginine induced penile erection by co-administration of L-NAME with L-arginine, the results of this study suggest that L-arginine/nitric oxide pathway may be involved in the neurotransmission of PVN activation-induced penile erection in the rat.     

Effects of intracavernosal trazodone hydrochloride: animal and human studies

Trazodone hydrochloride is an oral antidepressant agent which has been associated with the improvement of erections in impotent men and the development of prolonged erections or priapism in potent men. An in vivo study in animal and human subjects was performed to gain experience with the effect of intracavernosal trazodone. In the anesthetized New Zealand White rabbit, intracavernosal trazodone or its major metabolite m-chlorophenylpiperazine (m-CPP) produced full penile erection in 76% and 84% of animals studied respectively with doses ranging from one to 15 mg. On the other hand, intracavernosal administration of five mg. papaverine resulted in a prolonged erection in 90% of animals studied. In 13 selected volunteer patients, intracavernosal trazodone caused tumescence but not full penile erection with corporal body pressures of 28.2 +/- 5.8 mm. Hg. Intracavernosal papaverine or papaverine and phentolamine in these subjects resulted in significantly higher corporal body pressures of 58 +/- 18 mm. Hg (p less than .05). Intracavernosal administration of alpha adrenoceptor agonists but not normal saline resulted in complete detumescence of trazodone- or m-CPP-induced prolonged erection in the animal studies. Intracavernosal trazodone results in erectile activity that appears in part based on its local alpha blocking activity but like other intracavernosal alpha-blocking agents is not as effective in initiating penile erections as are intracavernosal agents that directly induce smooth muscle relaxation.     

Cavernosometry: corroboratory method to surgical treatment of impotence due to venous leakage

There are still controversies about the mechanism of penile erection. Arterial aspects of impotence have received considerable attention, but just recently the venous component became widely recognized. Twenty patients with abnormal cavernosometry (flow rate over 280 mL/min) and no rigid erections (intracavernosal pressure lower than 80 mm Hg) were analyzed. Surgical ligation of the dorsal veins was performed in 12 cases, 9 of which also required ligation of the crus of each corpus cavernosum. After these ligations, erection improved sufficiently to allow satisfactory intercourse in 9 of 12 patients. Two patients became impotent after eight months of normal sexual performance. The 3 failures showed persistently high flow rates and one leakage by the crural edge which had not been ligated at surgery. In selected patients with organic impotence the venous abnormalities should be assessed routinely and dorsal veins and the crural edge of the corpus cavernosum should be ligated in an attempt to restore erectile function.     

The veno-occlusive mechanism of the canine corpus cavernosum: angiographic and pharmacologic studies

Studies were designed to document the normal angiography and pressure-volume characteristics of the canine corpus cavernosum, evaluate the effects of various vasoactive agents, and characterize a veno-occlusive mechanism. In fourteen dogs, baseline cavernosography demonstrated venous drainage via six to ten tributaries arising from the crura and entering the deep penile veins. Control cavernosometry during infusion of saline at 0.33 ml./sec. led to a rise in intracavernosal pressure (ICP) from 24.9 +/- 7.9 mm. Hg to 68.4 +/- 21.1 mm. Hg. Intracavernosal injection of a number of vasodilators, including papaverine, nitroglycerin, acetylcholine, and prostaglandin E2, raised baseline ICP significantly, caused extreme elevation of pressure during saline infusion (greater than 450 mm. Hg), and narrowed or obliterated the venous lumena at the site of tunica perforation, as judged angiographically. These effects could be reversed with phenoxybenzamine or norepinephrine. Our results further support the current understanding of the canine veno-occlusive mechanism.     

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。     

Autonomic control and vascular changes during penile erection in monkeys

The mean pressure in the unstimulated corpus cavernosum of monkeys was 12.1 mm Hg. Pelvic nerve stimulation at 8 to 10 Hz produced penile extension and the mean pressure increased to 64.3 mm Hg (47-84% of carotid artery pressure) after a latency of 10 s. On stopping stimulation, recovery to resting levels occurred within 2 min. The response was not blocked by atropine or propranolol. Blood flow through two 19 gauge needles inserted into the corpus cavernosum increased in parallel with the pressure changes, indicating that arterial inflow increased. Stimulation of either hypogastric nerves or the sympathetic chain produced penile retraction but increased corpus cavernosal pressure. The response to pelvic nerve stimulation was partially blocked. It was concluded that both of these nerves contract penile erectile tissue within the corpus cavernosum and constrict arterial inflow.     

Comparison of oral and intracavernosal vasoactive agents in penile erection

This discussion summarizes the potential differences in physiologically and pharmacologically induced erections and highlights the possible differences in the pathways facilitated by oral versus intracavernosal agents in penile erection. Oral agents act in conjunction with sexual stimulation either increasing corporal smooth muscle relaxation or attenuating smooth muscle contraction. However, their efficacy is dependent on sexual stimulation. Intracavernosal administration of phosphodiesterase type 5 inhibitor (sildenafil) or short-acting alpha adrenergic receptor antagonist (phentolamine), in the absence of sexual stimulation, does not initiate penile erection. In contrast, intracavernosal administration of PGE1 or papaverine induces erection independent of sexual stimulation. Thus, oral agents are not direct mediators of smooth muscle relaxation and act to facilitate relaxation in response to sexual stimulation, while intracavernosal agents directly mediate smooth muscle relaxation, independent of sexual stimulation. Although, considerable advances have been made in elucidating the physiology and pharmacology of erectile function, details of the signal transduction pathways affected by these agents in the penile corpus cavernosum are yet to be fully investigated. International Journal of Impotence Research (2000) 12, Suppl 1, S81-S88     

A castrated mouse model of erectile dysfunction

To establish a mouse model for the study of venoocclusive erectile dysfunction, we investigated erectile function in wild-type (WT), castrated (CAST), and castrated mice receiving immediate testosterone replacement (TEST). Adult C57BL6 mice ( approximately 30 g) underwent electrical stimulation of the cavernous nerve in vivo (parameters: 16 Hz frequency, 5 ms duration, 4V stimulatory voltage) with intracavernosal pressure (ICP) monitoring. A total of 55 mice (5 WT, 25 CAST, and 25 TEST) were evaluated. CAST and TEST (5.0 mg/pellet, 60-day release) mice were divided into groups of 5 and evaluated at 24 hours, 72 hours, 1 week, 2 weeks, and 4 weeks. Penile tissue was immunohistochemically stained for alpha-actin (marker for smooth muscle cells) and CD-31 (marker for endothelial cells). Stained slides were analyzed using Image Pro-plus software. In secondary studies, a Doppler flow meter was employed to evaluate penile blood flow. ICP measurements (mm Hg) were significantly decreased in CAST mice at 24 hour-, 72 hour-, 1 week-, 2 week-, and 4-week time points compared with WT mice (41.9 +/- 14.9, 19.1 +/- 4.2, 17.5 +/- 8.2, 14.2 +/- 4.4, and 10.0 +/- 3.8, respectively, vs 50.2 +/- 2.8), but TEST animals maintained or had an increase in ICP in comparison with WT mice (48.0 +/- 1.4, 52.3 +/- 1.3, 60.8 +/- 7.6, 80.5 +/- 2.1, and 81.5 +/- 1.2, respectively). Mean systemic arterial pressure remained approximately 80 mm Hg irrespective of treatment. CAST mouse penis specimens revealed decreased alpha-actin and CD-31 immunoreactivity only at the 4-week interval, compared with WT and TEST specimens. Doppler ultrasound flow rates (centimeter per second), taken before, during, and immediately after cavernous nerve stimulation, were WT 45.4 +/- 7.3, 30.6 +/- 5.2, 55.3 +/- 8.2 vs CAST (2 weeks) 22.2 +/- 2.5, 25.0 +/- 1.5, 23.1 +/- 2.0 vs TEST (2 weeks) 30.5 +/- 6.5, 25.7 +/- 2.0, 45.2 +/- 4.5. This prominently showed that intrapenile flow was not reduced normally during erectile stimulation in CAST mice. This is the first described mouse model of castration-induced veno-occlusive erectile dysfunction. Erectile response abnormalities as measured by ICP and Doppler ultrasound studies in CAST mice may be attributed to hypogonadal effects on erectile tissue function. Morphologic changes in the cavernosal tissue of CAST mice coincide with these abnormalities to some extent. This study defines an androgen-dependent mechanism of veno-occlusive erectile function in the mouse. The castrated mouse model can be applied in future studies of veno-occlusive erectile dysfunction.     

血红素氧合酶2在去势大鼠阴茎海绵体内的表达

目的:研究去势大鼠阴茎海绵体血红素氧合酶2(HO-2)和内皮型一氧化氮合酶(eNOS)的表达,探讨雄激素与HO-2、eNOS在ED中的作用及相关性。方法:10周龄雄性SD大鼠40只,分为4、8、12周组和正常对照组各10只,实验组采取手术切除双侧睾丸,对照组采取假手术。分别于术后4、8、12周测定大鼠血清睾酮(T)、阴茎海绵体内压(ICP)、平均颈动脉压(MAP),取阴茎标本,采用Western印迹分析阴茎海绵体HO-2含量,免疫组化分析HO-2和eNOS的表达。结果:去势各组血清T水平较正常对照组显著下降(P<0.05)。经3V、5V电压刺激后去势各组ICP/MAP值明显下降(P<0.05)。HO-2在正常和去势大鼠阴茎海绵体组织均有表达,去势4周组HO-2光密度分布曲线下面积(341.50±99.70)较正常组(876±443.36)和去势8周组(705.00±152.74)明显下降(P<0.05),去势8周与正常组之间无显著变化(P>0.05),去势12周没有检测到HO-2的表达。eNOS主要表达于阴茎海绵体血管内皮细胞,去势组eNOS(123.94±30.23)较正常组(421.21±125.12)差异有显著性(P<0.05)。T与eNOS和HO-2表达呈高度正相关(r=0.976、0.946,P均<0.05)。结论:雄激素可能通过影响大鼠阴茎海绵体HO-2、eNOS的表达参与阴茎勃起功能调控。     

Nitric oxide synthase gene transfer for erectile dysfunction in a rat model

OBJECTIVE: To determine whether over-expression of nitric oxide synthase (NOS) in the corpus cavernosum of the penis improves erectile function, as NO is an important transmitter for genitourinary tract function, mediating smooth muscle relaxation and being essential for penile erection. MATERIALS AND METHODS: The inducible form of the enzyme NOS (iNOS) was introduced into the corpus cavernosum of adult Sprague-Dawley rats (250-300 g) by injecting a solution of plasmid, adenovirus or adenovirus-transduced myoblast cells (adeno-myoblasts). Plasmid, adenovirus and adeno-myoblasts encoding the expression of the beta-galactosidase reporter gene were also injected into rats. RESULTS: Throughout the corpora cavernosum there was expression of beta-galactosidase after injecting each of the three solutions. Maximum staining was greatest for adeno-myoblast, then adenovirus and then plasmid. The mean (sd) basal intracavernosal pressure (ICP) of iNOS-treated animals (adenovirus and adeno-myoblast) increased to 55 (23) cmH2O, compared with naive animals with a basal ICP of 5 (6) cmH2O (P = 0.001). Stimulating the cavernosal nerve (15 Hz, 1.5 ms, 10-40 V, 1 min) resulted in a doubling of the ICP (adenovirus and adeno-myoblast) from the basal level of the iNOS-treated animals. Direct in situ measurement of NO showed the release of 1-1.3 micro mol/L in the adeno-myoblast penis. CONCLUSION: Myoblast-mediated gene therapy was more successful for delivering iNOS into the corpus cavernosum than direct adenovirus injection or plasmid transfection. Surprisingly, implanting muscle cells into the penis is not only feasible but also beneficial. Gene therapy for NOS may open new avenues of treatment for erectile dysfunction. Control of NOS expression would be necessary to prevent priapism.     

Normal hemodynamic parameters do not always predict the presence of a rigid erection: a quantitative assessment of functional erectile impairment

The purpose was to assess objectively and quantitatively the hemodynamic status and the degree of functional erectile impairment in a group of impotent patients. A clinical study was designed, incorporating pharmacocavernosometry (to evaluate arterial and veno-occlusive function) with axial buckling forces and penile geometry measurements in a group of impotent patients. The pressure gradient between the intracavernosal pressure associated with the presence of penile axial rigidity and the equilibrium intracavernosal pressure was calculated (axial rigidity gradient, ARG); such methodology allowed a quantitative characterization of functional impairment, as ARG expresses the intracavernosal pressure increase necessary to achieve axial rigidity and therefore potency. Penile geometry characteristics were also expressed by calculating the penile aspect ratio (diameter/length, D/L). In 83 consecutive patients tested (mean age 42.89+/-9.96), rigidity occurred at intracavernosal pressures between 50 and 100 mm Hg. A conversely proportional relation was noticed between penile aspect ratio values and the intracavernosal pressure associated with rigidity values, clearly demonstrating the important functional role of penile geometry. ARG demonstrated a wide range of values (3-69 mm Hg), reflective of the severity of the erectile dysfunction on each patient. Half (50.6%) of the patients had ARG values < or =20 mm Hg, indicative of minimal and minimal-to-moderate erectile impairment, while 20.48% had ARG between 21-30 and 28.92% >30 mm Hg, indicative of moderate and severe erectile dysfunction (ED) respectively. In all, 6% of the study group, all of them with primary ED, ARG <20 mm Hg had normal hemodynamics, but low penile aspect ratio values indicating that penile geometry may be the cause of insufficient rigidity. Hemodynamic integrity is the most critical, but not the only determinant of penile rigidity, as erectile impairment may be noticed in patients with normal arterial inflow and corporal veno-occlusive function. In such cases, unfavorable penile geometry should be considered as the possible etiological factor of impotence.     

Pathophysiology of prolonged penile erection associated with trazodone use

Treatment with the antidepressant trazodone has been associated with the occurrence of prolonged penile erection and priapism. To evaluate the effect of trazodone on erection we monitored the periodic physiological sleep-related erections in 6 healthy volunteers in a double-blind crossover study comparing the effect of trazodone, trimipramine (a tricyclic antidepressant) and placebo. In addition, to determine the effects of trazodone on the neurovascular control of penile smooth muscle we performed in vitro studies on corpus cavernosum tissue obtained from patients undergoing penile prosthesis implantation. Trazodone significantly increased the total interval of nocturnal erectile activity, while trimipramine had no effect. During the high dose treatment (nights 4 and 5) the average duration of erectile activity per night with placebo was 158 +/- 41 minutes (mean +/- standard deviation) for night 4 and 177 +/- 21 minutes for night 5. During trazodone treatment the erectile activity per night was significantly prolonged to 285 +/- 115 minutes during night 4 and 232 +/- 86 during night 5 (p less than 0.01). Analysis of the erectile activity in relation to the rapid eye movement sleep period during which erectile activity usually occurs revealed that the detumescence phase of erection, under sympathetic control, was significantly prolonged an average of 2.4 times by trazodone compared to placebo (p less than 0.05). In vitro, trazodone at concentrations comparable to those reached in plasma significantly impaired corporeal smooth muscle contractions elicited by electrical stimulation of adrenergic nerves and antagonized contractions induced by exogenous norepinephrine. We conclude that trazodone can enhance penile erection in man and propose a mechanism related to the alpha-adrenoceptor blocking properties of trazodone by interference with the sympathetic control of penile detumescence.     

Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno-occlusive dysfunction in androgen deficiency

Androgens are deemed to be critical for the development, growth, and maintenance of penile tissue as well as for erectile function. Androgens are also reported to inhibit differentiation of stroma progenitor cells into adipocytes and promote differentiation into smooth muscle. The objective of this study was to investigate whether androgen deprivation results in accumulation of adipocytes in the corpus cavernosum. Mature, New Zealand white male rabbits were subjected to sham surgery (control) or orchiectomy. Two weeks after surgery, erectile function was assessed by monitoring changes in intracavernosal blood pressure (ICP) in response to pelvic nerve stimulation. All ICP measurements were normalized to the mean systemic arterial blood pressure. In parallel studies, penile cross sections from control and orchiectomized rabbits were fixed and stained with either Masson's trichrome or hematoxylin and eosin to assess smooth muscle and connective tissue content. Alternatively, tissue sections were stained with Toluidine blue to assess accumulation of fat-containing cells. Orchiectomy resulted in loss of erectile function and penile atrophy, associated with reduced trabecular smooth muscle and increased connective tissue content. Most strikingly, tissue from orchiectomized animals exhibited accumulation of fat-containing cells (adipocytes) in the subtunical region of the corpus cavernosum. We hypothesize that androgen deprivation promotes differentiation of progenitor stroma cells into an adipogenic lineage producing fat-containing cells, thus altering erectile function.     

The effects of androgen on penile reflex, erectile response to electrical stimulation and penile NOS activity in the rat

Aim: To investigate the effects of androgen on penile erection through the reflex arc and penile corpus cavernosum,and study the respective roles of testosterone (T) and dihydrotestosterone (DHT) in penile erection ira rats. Methods:Male Sprague-Dawley rats were castrated and implanted with silastic brand silicone tube containing T or DHT, with orwithout daily injections of a 5a-reductase inhibitor, MKM-434. The penile reflex, erectile response to electrical stimula-tion (ES) of the cavernous nerves and penile nitric-oxide synthase (NOS) activity were observed under varying andro-genic status. Results: Penile reflex erection in the rat was, on the whole, related to serum T levels though the numberof glans engorgernents was not. The number of cups and flips was significantly decreased by castration, and restoredto the control level by T supplementation. Erectile response to ES and NOS activity in penile tissue was also related toserum T level. T administered together with a ,5a-reductase inhibitor no longer restored the number of reflex erection,erectile responses to ES and NOS activity in the corpus cavemosum. Conclusion: Androgen influenced the penile re-flex arc, corpus cavemosum, and the perinea] striated muscles, ha reflex erection, erectile response to ES and penileNOS activity in the rat, T seeras to be first conyerted to DHT, the more active androgen modality. (Asian JAndrol1999Dec; 1: 169-174)