The Anatomy and Embryology of Posterior Urethral Valves

Urology, 2001

Objectives. To determine the effect of experimental hypercholesterolemia on the ultrastructure of cavernosal smooth muscle cells, endothelial cells, elastic fibers, and collagen content, which are the key structures fundamental for erection. Methods. Forty-two New Zealand white rabbits were divided into a control group (group 1, n ϭ 7, fed a standard diet), a hypercholesterolemia group (group 2, n ϭ 20, fed a diet containing 1% cholesterol for 8 weeks), and a reversibility group (group 3, n ϭ 15, fed a 1% cholesterol diet for 8 weeks, then switched to a standard diet for 4 weeks). Blood samples were obtained for lipid determination before and after the study. The cavernosal tissues were obtained at the end of 8 weeks for groups 1 and 2 and at the end of 12 weeks for group 3 and immunohistochemical examinations of these cells were performed. Results. Immunohistochemical analysis revealed that hypercholesterolemia produces marked and reversible decreases in the cavernosal content of smooth muscle cells, endothelial cells, and elastic fibers and increases the content of collagen 3 and 4. Conclusions. Our findings suggest that hypercholesterolemia in this animal model affects the percentage of staining for smooth muscle actin, endothelial cells, elastin, and collagen 3 and 4. However, since this effect is temporary depending on the blood cholesterol levels, it might not alter the erectile function.

Journal of Urology, 1998

Purpose: Reliable, clinically available, non-invasive measurements able to predict trabecular histology without the need for erectile tissue biopsy would improve impotence management, since the percentage of trabecular smooth muscle content has been shown to be associated with corporal veno-occlusive dysfunction. The purpose was to identify whether the erectile tissue mechanical property, cavernosal expandability, correlated with the percentage of trabecular smooth muscle content in an animal model of hypercholesterolemia and ischemic-induced corporal fibrosis. Materials and Methods: New Zealand White rabbits (6 to 7 months old, 3 to 3.5 kg.), were divided into control (n = 71, hypercholesterolemic (n = 5, 0.5% cholesterol diet) and atherosclerotic groups (n = 8, 0.5% cholesterol diet with balloon de-endothelialization). At 16 weeks, the corpora cavernosa were removed en bloc and submerged in physiologic salt solution, and volumepressure data were plotted at 20 mm. Hg pressure intervals under trabecular smooth muscle relaxation. Cavernosal expandability, X, (the measure of the ability to achieve high corporal expansion at relatively low intracavernosal pressure) and tunical distensibility, VENF, (relative volume of fully erect to flaccid penis) were calculated. Erectile tissue was assessed by computerassisted color histomorphometry with Masson's trichrome stained sections (30 to 45 high power fielddanimal) to assess percentage of trabecular smooth muscle content. Results: The overall mean percentage of trabecular smooth muscle content and mean cavernosal expandability values were 45.4 % 1.6, 39.2 ? 0.9, 33.9 ? 0.6 and 0.0165 ? 3.04 X lop3, 0.0116 2 1.63 x 0.0118 % 1.26 X lop3 mm. Hg-' for the control, hypercholesterolemic and atherosclerotic groups, respectively (r = 0.87). Significant differences in trabecular smooth muscle content were observed among all 3 groups, and in cavernosal expandability, between control and atherosclerotic groups, as well as between control and hypercholesterolemic groups but not between atherosclerotic and hypercholesterolemic groups. Conclusions: The erectile tissue mechanical property, cavernosal expandability, correlated with erectile tissue structural quality. Since cavernosal histology has been shown to predict corporal veno-occlusive function, it is hypothesized that the measurement of cavernosal expandability may become a valuable functional clinical parameter in the diagnosis and treatment of men with erectile dysfunction.

Urology, 2006

Objectives. To evaluate how the expression of angiogenic factors and their downstream target molecules, which are potentially involved in penile homeostasis, is related to erectile dysfunction in a rat model of hypercholesterolemia. Methods. Fifty-six 2-month-old male Sprague-Dawley rats were included in this study. The control animals (n ϭ 28) were fed a normal diet, and the experimental animals (n ϭ 28) were fed a diet containing 4% cholesterol and 1% cholic acid for 3 months. Erectile function was evaluated by cavernous nerve electrical stimulation, and cavernous tissue was harvested for histologic examination (n ϭ 12, respectively). Cavernous tissue specimens from the remaining rats were used for reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, or cyclic guanosine monophosphate (cGMP) measurement. Results. The ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the hypercholesterolemic rats than in the controls (P Ͻ0.01). Analysis by RT-PCR and Western blot showed significantly lower gene expression of vascular endothelial growth factor (VEGF), angiopoietin-1, and angiopoietin-2 and significantly lower protein expression of VEGF, angiopoietin-1, angiopoietin-2, the ratio of phospho-Akt to Akt, and phospho-endothelial nitric oxide synthase (eNOS) to eNOS in hypercholesterolemic rats than in controls. Cavernous tissue cGMP concentrations and endothelial area were also significantly lower in hypercholesterolemic rats than in controls (P Ͻ0.01). Conclusions. Downregulation of the expression of the angiogenic factors and their downstream signal molecules, and decreased endothelial content in the corpus cavernosum of hypercholesterolemic rats might play important roles in the deterioration of erectile function.

Urology, 2006

To determine the effect of long-term experimental hypercholesterolemia on cavernosal tissues and to evaluate whether these alterations are reversible after improvement of hypercholesterolemia. Methods. Thirty-seven New Zealand male rabbits with a mean age of 5 to 6 months and a weight of 2 to 2.5 kg were included in this study. The control group (group 1, n ϭ 7) was fed with normal standard rabbit chow for 24 weeks, the hypercholesterolemia group (group 2, n ϭ 17) was fed with a 1% pure cholesterol diet for 24 weeks, and the reversibility group (group 3, n ϭ 13) was fed first with the 1% pure cholesterol diet for 24 weeks and then with normal standard rabbit chow for 12 weeks. The basal and 24-week serum lipid profiles of all groups and the 36-week serum lipid profiles of group 3 were measured. Core tissue samples 4 mm in diameter taken from formalin-fixed, paraffin-embedded tissue blocks of rabbit corpus cavernosum were examined for Masson trichrome histochemically and desmin and smooth muscle actin by the tissue array method using immunohistochemistry. Results. Hypercholesterolemia was observed in groups 2 and 3 at 24 weeks compared with group 1. In group 3, at 36 weeks, the cholesterol levels were decreased. A statistically significant (P Ͻ0.05) irreversible decrease was observed in smooth muscle actin level in group 3 (reversibility group) by immunohistochemical analysis. The decrease in desmin was reversible, and no significant difference was observed in collagen among the three groups. Conclusions. Long-term chronic effects of experimental hypercholesterolemia on cavernosal smooth muscles might be irreversible and this might alter erectile function. UROLOGY 67: 431-434, 2006.

Journal of Sexual Medicine, 2009

Introduction. Endothelial cell-to-cell junctions are crucial for vascular formation, networking, and remodeling of blood vessels as well as for inducing and integrating intracellular signals. Aim. We investigated the differential expression and distribution of endothelial cell-to-cell junction proteins in the penis of mice with hypercholesterolemia-induced erectile dysfunction. Methods. Two-month-old C57BL/6J mice were fed a diet containing 4% cholesterol and 1% cholic acid, and age-matched control animals were fed a normal diet, for 3 months. We performed dual priming oligonucleotide (DPO)-based multiplex polymerase chain reaction (PCR) (Seegene, Seoul, Korea) to screen the differential gene expression of 21 endothelial cell-to-cell junctions. Main Outcome Measures. At 5 months, erectile function was measured by electrical stimulation of the cavernous nerve, and the penis was harvested and stained with antibody to claudin-5, vascular endothelial (VE)-cadherin, and platelet/endothelial cell adhesion molecule (PECAM)-1 (N = 8 per group). Cavernous specimens from a separate group of animals were used for claudin-5, VE-cadherin, and PECAM-1 reverse transcriptase-PCR and Western blot analysis. Results. Erectile function was significantly lower in hypercholesterolemic mice than in controls. DPO-based multiplex PCR revealed a profound decrease in the gene expression of endothelium-specific cell-to-cell junction proteins, including claudin-5, VE-cadherin, and PECAM-1, in hypercholesterolemic mice compared with that in controls. The expression of claudin-5, VE-cadherin, and PECAM-1 protein evaluated by Western blot or immunohistochemistry was significantly lower in hypercholesterolemic mice than in controls. These endothelial cell-tocell junction proteins were more sparsely distributed in the endothelium of cavernous sinusoids than in the endothelium of cavernous artery and dorsal blood vessels. Conclusion. Down-regulation of the endothelial cell-to-cell junctions and decreased endothelial content in the corpus cavernosum might play a major role in the deterioration of erectile function in hypercholesterolemic mice.

The Journal of Urology, 1998

Purpose: To determine the effects of hypercholesterolemia and atherosclerosis-induced chronic cavernosal arterial insufficiency on cavernosal smooth muscle tone, nitric oxide synthase (NOS) activity and cavernosal tissue synthesis of constrictor eicosanoids. To study whether inhibition of the cyclooxygenase pathway by indomethacin and tissue treatment with nitric oxide (NO) precursor L-arginine improve hypercholesterolemia and ischemia-induced impaired endothelium-dependent and neurogenic relaxation of cavernosal tissue. Materials and Methods: New Zealand White rabbits were divided into control (n = 10, fed a regular diet), hypercholesterolemia (Hch, n = 13, fed a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 14) groups. The CCI group underwent balloon deendothelialization of iliac arteries and received a diet containing 0.5% cholesterol. After 16 weeks, we examined the effects of Hch and balloon de-endothelialization induced arterial occlusive disease on iliac arterial blood flow, reactivity of cavernosal tissue, cavernosal NOS activity and cavernosal tissue synthesis of constrictor eicosanoids. Results: Histology revealed significant atherosclerotic arterial occlusive disease in the CCI group. Iliac artery blood flow in the CCI group was significantly reduced compared with the control and Hch groups. In the Hch and CCI groups, endothelium-dependent relaxation of cavernosal tissue to acetylcholine was significantly reduced compared with the control group. Electrical field stimulation-induced neurogenic relaxation and cavernosal NOS activity were significantly reduced in the CCI group but not in the Hch group. The basal release of cavernosal constrictor eicosanoids, prostaglandin F,, (PGF,,) and thromboxane A, (TXA,) was significantly increased in the CCI group. Indomethacin increased endothelium-dependent relaxation in all groups and neurogenic relaxation in the CCI group, but failed to normalize the differences in relaxation between treated and control groups. In the presence of indomethacin, L-arginine improved endothelium-dependent relaxation of cavernosal tissue in the Hch group but did not normalize endothelium-dependent or neurogenic relaxations in the CCI group. Relaxation to NO donor sodium nitroprusside and papaverine was similar in cavernosal tissue from all groups. Conclusions: Impairment of endothelium-dependent relaxation by Hch occurs secondary to disruption of the NO formation in cavernosal endothelium. Improvement of endotheliumdependent relaxation by L-arginine may suggest lack of availability of L-arginine in cavernosal tissue from the Hch animals. Impairment of endothelium-dependent and neurogenic relaxation by CCI occurs secondary to disruption of the NO formation due to an alteration in the expression or activity of NOS and increased output of constrictor eicosanoids in cavernosal tissue. These studies show that Hch and atherosclerosis-induced chronic cavernosal arterial insufficiency, beyond decreasing cavernosal perfusion pressure, also adversely affect smooth muscle relaxation mechanisms in cavernosal tissue.

American journal of hypertension, 2000

Erectile dysfunction has an increased prevalence in hypertensive patients and is associated with cardiovascular diseases. For many years the discussion has been polarized on whether in hypertensive patients, it is the arterial hypertension or the antihypertensive therapy that is the cause of male erectile dysfunction. The aim of our study was to determine the morphologic changes in cavernous tissue (CT) in an animal model of arterial hypertension. Male spontaneously hypertensive rats (SHR) (n = 15) and normotensive Wistar-Kyoto (WKY) rats (n = 15) were studied for 8 months. Animals were allowed to drink tap water and fed a standard rat chow ad libitum. Systolic blood pressure (SBP) was measured monthly by the tail/cuff method. At the end of the experiment all the animals were sacrificed for microscopic studies. Cavernous tissue was processed by hematoxylin and eosin, Masson's trichrome, and monoclonal anti-alpha smooth muscle actin. Cavernous smooth muscle (CSM) and vascular smo...

Urologia Internationalis, 2010

Objective: The aim of this study was to evaluate the acute effects of a high cholesterol diet (HCD) on erectile and endothelial functions in Sprague-Dawley rats. Materials and Methods: Sprague-Dawley rats were divided into 2 groups as control and HCD groups. The control group was fed on a normal diet and the hypercholesterolemia group was fed a 1% cholesterol-enriched diet daily for 2 weeks. Total cholesterol levels were measured at the end of 2 weeks in both groups. To examine the effect of HCD on erectile function, electric cavernous nerve stimulation (CNS) at 20 Hz with a pulse duration of 1 ms for 1 min at 5 V was performed. During CNS, we measured intracavernous pressure (ICP), mean arterial pressure (MAP), detumescence time and area under the curve (AUC). To evaluate the endothelial responses, acetylcholine (Ach) was applied cumulatively (1 nM to 1 µM) to thoracic aorta tissues contracted with 60 mM KCl. Results: In the HCD group total cholesterol levels were significantly hig...

American journal of hypertension, 2004

Male erectile dysfunction is increased in prevalence in patients with hypertension. Previous experiments from our group demonstrated morphologic changes in erectile tissue from male spontaneously hypertensive rats (SHR). The aim of the present study was to determine whether blood pressure (BP) control is enough to preserve cavernous tissue from the deleterious effect of arterial hypertension. Eight-week-old male SHR and normotensive Wistar-Kyoto rats (WKY) were studied during 6 months: Group 1 (n = 10) SHR; group 2 (n = 10) SHR with 7.5 mg/kg/d candesartan (C); group 3 (n = 10) SHR with 100 mg/kg/d atenolol (AT); and group 4 (n = 10) WKY. At the end of the experiment all the animals were killed for microscopic studies. Cavernous tissue was processed by hematoxylin-eosin, Masson's trichrome, monoclonal anti-alpha-smooth muscle actin, and anticollagen type III. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries and the amounts of collagen type I...

International Journal of Impotence Research, 2008

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through a 1 -and a 2 -postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through a 2 -presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y 1 -and Y 2 -postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of a 1 -adrenoceptors involves both Ca 2 þ influx through L-type and receptor-operated Ca 2 þ channels (ROC) and Ca 2 þ sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca 2 þ entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3 0 -monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K þ efflux through Ca 2 þ -activated (K Ca ) and voltage-dependent Ca 2 þ (K v ) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca 2 þ sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K þ efflux through ATPsensitive K þ (K ATP ) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitationsecretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.