Intracorporeal Pressure Research Articles

Hypospadias-associated penile curvature assessment and management: A global survey of current practice

Our goal was to assess how surgical management of hypospadias-associated penile curvature (HAPC) varies across continents, focusing on factors that influence assessment and decision-making. Members of the European Society of Pediatric Urology (ESPU), Society of Pediatric Urology (SPU), and Hypospadias International Society (HIS) participated in an anonymous, 34-question online survey addressing pre-, intra-, and postoperative elements of HAPC evaluation and management. A selection of intraoperative photos were included in the survey to investigate the prevailing surgical approaches and identify management patterns. Out of the 267 participants, 38.4% of them are located in Europe. Visual estimation was the predominant approach for evaluating HAPC, although being regarded as the least dependable compared to other techniques. Surgeons who performed more than 40 cases per year were more inclined to use goniometers and had varying degrees of HAPC that were considered acceptable without requiring any correction (P<.001). Out of 58% of respondents, a significant number reported regular utilization of artificial erection tests for all categories of hypospadias. Surgeons with fewer than 10 years of expertise commonly utilized erection test as part of their regular practice. A tourniquet was employed to maintain sufficient intra-corporeal pressure, by134 (50%). 116 participants (43%) inject Saline through the corpora cavernosa through the glans, while 150 (56%) administer saline from the lateral aspect. Moreover, the decision-making process differed based on the intraoperative picture scenarios of mild to moderate penile curvature during erection testing. Contrary to temperatures ranging from 25o to 35o, decision-making in cases with less severe degrees of HAPC was uncomplicated. This survey reveals a wide range of surgical practicepatterns in the assessment and management of HAPC. To our knowledge, this global surveyof HAPC practice is the largest to date and could aid in developing new guidelines in pediatricurology. These findings may also provide a foundation for future prospective multinational studies.

(094) Synergy Between Orally Administered Phosphodiesterase-type-5-inhibitors and Topically Delivered Nitric-oxide in Eliciting Erectile Responses

Abstract Introduction Phosphodiesterase-type-5-inhibitors (PDE5i) represent first-line FDA-approved oral treatments for erectile dysfunction (ED). However, because their mode of action is dependent on the production of nitric oxide (NO) from nerve endings, patients that suffer neurogenic ED (for example, following the procedures for radical prostatectomy (RP) or resulting from diabetes) are commonly refractory to PDE5i treatment. We recently demonstrated proof-of-principle for increased efficacy of topically applied NO-releasing microparticles (NO-MP) in eliciting an erectile response when used in combination with the orally administered PDE5i, sildenafil. However, there are several other FDA approved PDE5i used to treat ED, which, although acting through the common mechanism of PDE5 inhibition, exhibit several characteristics that potentially could impact clinical and commercial translation of combination therapy. Objective The goal of the present studies was to determine if other commercially available PDE5i besides sildenafil (avanafil, tadalafil and vardenafil) also act cooperatively when used in combination with NO-MP to elicit an erectile response. Methods Sprague-Dawley rats underwent bi-lateral transection of the cavernous nerve (CN), as a model of RP, one-week prior to determining erectile response to treatment. We investigated the effect of oral administration of 0.05mg sildenafil/kg, 0.005mg tadalafil/kg, 0.01mg vardenafil/kg and 0.1mg avanafil/kg (approximately equivalent to clinical doses of 2.5mg, 0.25mg, 0.5mg and 5mg, respectively, administered to an 80 kg patient) 30 minutes prior to being anesthetized for the determination of erectile response by intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 minutes, at which time 100 mg of NO-MP (or control, blank-MP) were applied to the rat penile shaft. The ICP and systemic BP were used to determine the time to the first erectile response, duration of the erectile responses, the maximal and average ICP/BP responses and the number of spontaneous erections per hour. Results Although oral treatment by PDE5i alone resulted in no observable erectile response, topical application of NO-MP resulted in spontaneous erectile responses. When NO-MP were applied in combination with oral PDE5i treatment, all PDE5i resulted in faster times to the first erectile response (on average 11 minutes compared to 22 minutes when NO-MP were used alone; P-value=0.041) and greater numbers of spontaneous erections (on average 4.6 erections per hour compared to 2.0 when NO-MP were used alone, P-value=0.043). Although there were no significant differences between any of the PDE5i when used in combination with NO-MP with respect to the average erectile responses per hour, duration of erectile response, and maximal ICP/BP, there was a trend in the vardenafil and avanafil treated animals for a more rapid onset of the erectile responses than observed with sildenafil and tadalafil. Conclusions Although knowledge of the molecular pathways that lead to an erection provide a rationale for a synergistic effect between PDE5i and NO in eliciting an erectile response, our results provide the first evidence of such synergy. Our results suggest a novel treatment strategy for patients with ED refractory to PDE5i, namely any of the FDA-approved oral PDE5 inhibitors used in combination with formulations that topically deliver NO to corporal tissue. Disclosure Yes, this is sponsored by industry/sponsor: Zylo Therapeutics, Inc Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Zylo Therapeutics, Inc

Characterization of a novel rabbit model of Peyronie's disease.

Peyronie's disease (PD) is a debilitating pathology which is associated with penile curvature and erectile dysfunction due to the formation of fibrotic plaques in the penile tunica albuginea. In the present study, we developed a novel rabbit model of PD via subtunical injection of recombinant transforming growth factor (TGF)-β1 protein and characterized erectile function and histopathological endpoints following plaque formation. Ten adult male, New Zealand white rabbits were randomized into 3 experimental groups including nonsurgical controls (NSC, N = 3) and those receiving subtunical injections of vehicle (N = 3) or TGF-β1 protein (0.5 µg/50 µl; N = 4). Following 1 month post-op, focal fibrous plaques composed of disorganized collagen type I and III bundles as well as fragmented elastin fibers at TGF-β1 injection sites were observed in contrast to control groups. Cavernosometric and cavernosographic evaluations revealed no significant differences in maximum intracorporal pressures or substantial curvature during papaverine-induced erection in either the vehicle or TGF-β1 cohorts. Immunohistochemical and histomorphometric analyses demonstrated significant increases in elastase 2B expression in TGF-β1-induced plaques as well as significant declines in matrix metalloproteinase (MMP)-2 and -9 expression relative to control levels. Our results demonstrate that PD-like fibrotic plaques can be created in the rabbit penile tunica albuginea following TGF-β1 injection.

Synergy Between Sildenafil and Topically Delivered Nitric-oxide in Eliciting an Erectile Response in a Rat Model of Radical Prostatectomy

ABSTRACT Introduction Sildenafil belongs to a group of phosphodiesterase-type-5-inhibitors (PDE5i) which represent the only class of FDA-approved oral treatments for erectile dysfunction (ED). However, because their mode of action is dependent on the production of nitric oxide (NO) from nerve endings, patients that undergo radical prostatectomy (RP), which results in cavernous nerve (CN) injury, are commonly refractory to these pharmacologic agents. Objective Our goal was to investigate the ability of topically applied microparticles capable of transdermal delivery of NO (NO-MP) to act synergistically with sildenafil in eliciting an erectile response in an animal model of RP. Methods As a model of RP, Sprague-Dawley rats underwent bi-lateral transection of the CN one-week prior to determining erectile response to treatment. Rats were treated by oral gavage of 0.05 and 0.005 mg sildenafil/kg, 30 minutes before being anesthetized for the determination of intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 min, at which time 250 or 100 mg NO-MP (or control, blank-MP) were applied to the rat penile shaft. The ICP and systemic BP were used to determine the time to the first erectile response, duration of the erectile responses, the maximal and average ICP/BP responses and the number of spontaneous erections per hour. Results Although oral treatment with sildenafil by itself resulted in no observable erectile response, topical application of NO-MP in combination with sildenafil resulted in both a faster time to the first erectile response and greater numbers of spontaneous erections compared to NO-MP used alone. Combination of orally administered 0.05 sildenafil/kg with topical application of 250mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p-value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 minutes; t-test, p-value = 0.041). Conclusions Although knowledge of the molecular pathways that lead to an erection provide a rationale for a synergistic effect between PDE5i and NO in eliciting an erectile response, our results provide the first evidence of such synergy. When combined with the NO-MP, this synergy in eliciting an erectile response was seen with 0.05 mg sildenafil/kg, which would be equivalent to a clinical dose of approximately 2.5 mg sildenafil for an 80 kg patient. Our results suggest a novel treatment strategy for patients with ED following RP whereby an oral PDE5i is used in combination with therapeutics that topically deliver NO to corporal tissue and also the potential to lower the therapeutic dose of oral PDE5i in all patients where it is used for the treatment of ED. Disclosure Yes, this is sponsored by industry/sponsor: ZyloTherapeutics, Inc. Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: ZyloTherapeutics, Inc

Evaluation of Bi-Layer Silk Fibroin Grafts for Penile Tunica Albuginea Repair in a Rabbit Corporoplasty Model.

The use of autologous tissue grafts for tunica albuginea repair in Peyronie’s disease and congenital chordee is often restricted by limited tissue availability and donor site morbidity, therefore new biomaterial options are needed. In this study, bi-layer silk fibroin (BLSF) scaffolds were investigated to support functional tissue regeneration of tunica albuginea in a rabbit corporoplasty model. Eighteen adult male, New Zealand white rabbits were randomized to nonsurgical controls (NSC, N = 3), or subjected to corporoplasty with BLSF grafts (N = 5); decellularized small intestinal submucosa (SIS) matrices (N = 5); or autologous tunica vaginalis (TV) flaps (N = 5). End-point evaluations were cavernosography, cavernosometry, histological, immunohistochemical, and histomorphometric assessments. Maximum intracorporal pressures (ICP) following papaverine-induced erection were similar between all groups. Eighty percent of rabbits repaired with BLSF scaffolds or TV flaps achieved full rigid erections, compared to 40% of SIS reconstructed animals. Five-minute peak erections were maintained in 60% of BLSF rabbits, compared to 20% of SIS and TV flap reconstructed rabbits. Graft perforation occurred in 60% of TV group at maximum ICP compared to 20% of BLSF cohort. Neotissues supported by SIS and BLSF scaffolds were composed of collagen type I and elastin fibers similar to NSC. SIS and TV flaps showed significantly elevated levels of corporal fibrosis relative to NSC with a corresponding decrease in corporal smooth muscle cells expressing contractile proteins. BLSF biomaterials represent emerging platforms for corporoplasty and produce superior functional and histological outcomes in comparison to TV flaps and SIS matrices for tunica albuginea repair.

Long-term consequences of bilateral cavernous crush injury in normal and diabetic rats: a functional study.

A recent statement from the European-Society-for-Sexual-Medicine has highlighted the limitations of using the rat model for nerve-sparing prostatectomy. The use of young rats with no comorbidities and the early evaluation of the erectile function (EF) are deemed a source of bias. Our aim was to evaluate the long-term consequences in EF of bilateral nerve cavernous crush- injury (BNCI) in type 1 diabetic (DM) rats 30-male/12-week-old rats were divided into four groups: Sham, BNCI, DM, and BNCI + DM. Sham group underwent an intraperitoneal injection (IP) of saline solution and after 1 month underwent a sham laparotomy. BNCI underwent an IP of saline solution and after 1 month to BNCI. DM underwent an IP of 60 mg/kg-1-streptozotocin (STZ) and after 1 month to a sham laparotomy. BNCI + DM underwent an IP of 60 mg/kg-1-STZ and after 1 month to BNCI. After 5 months from the induction of diabetes, all rats underwent measurement of intracorporeal pressure (ICP) and mean arterial pressure (MAP) during CN-electrostimulation. Multiple groups were compared using Kruskal-Wallis one-way analysis of variance followed by Mann-Whitney U test for post hoc comparisons. Blood glucose-level was higher (p < 0.05) in the groups with DM and BNCI + DM. After 5-months, DM and BNCI + DM also showed a lower weight compared to other groups (p < 0.05). No differences were noted in ICP/MAP between the sham and BNCI. BNCI + DM showed lower ICP/MAP compared to all the groups (p < 0.05). DM Showed lower ICP/MAP compared to Sham and BNCI (p < 0.05). BNCI in rats without comorbidities did not induce long-term erectile dysfunction (ED) suggesting a spontaneous EF recovery. BNCI in DM induced long-term ED. The results of previous short-term studies can only provide evidence on the time to recovery of spontaneous EF as to the actual EF recovery rate.

A grade 1 titanium capacitive microsensor for continuous pressure monitoring of intracorporal pressures

Long-term implantable pressure monitoring is a key clinical parameter bringing a lot to clinicians by helping them treating many chronical diseases (e.g. glaucoma, hydrocephalus or heart failure). However for decades and up to now, most of the implantable sensors exhibited poor technological and clinical success due to the long-term biocompatibility constraints of the transducing part. The prime novelty of this paper is to propose a functional implantable MEMS pressure sensor with a bulk-micromachined titanium (Ti) transducer. Thanks to its small size, the active part of the sensor is thought versatile enough to be integrated in an active implantable device for measuring various intracorporal pressures. The transducer is made out of grade 1 Ti, which is one of the metalic materials of choice to insure long-term biocompatibility and has been proved to be a reliable material in the implantable industry. The uniqueness of the proposed sensor comes from its micromachining. The transducer, including a bulk titanium membrane, has been obtained through subtractive machining techniques benefiting from the extensive research experience on silicon MEMS. This Ti-based technology avoids the use of additionnal costly, complex and bulky encapsulation step to get a biocompatible device, thus enabling higher miniaturization level of implantable devices and lower rate of long term drift risks thanks to its monolithic architecture. The presented Ti MEMS sensor exhibits 1 fF mmHg−1 sensitivity within a clinically relevant pressure range of 0–300 mmHg, which is compatible with off the shelf low-power readout electronics.

Topically delivered nitric oxide acts synergistically with an orally administered PDE5 inhibitor in eliciting an erectile response in a rat model of radical prostatectomy.

Patients undergoing radical prostatectomy (RP) have a high incidence of post-operative erectile dysfunction (ED) refractory to treatment by oral phosphodiesterase-type-5-inhibitors (PDE5i). In the present studies, we investigated if a topically applied, nitric oxide microparticle delivery system (NO-MP) might act synergistically with an oral PDE5i (sildenafil) to improve erectile function outcomes in a rat model of RP.Thirty-five Sprague–Dawley rats underwent bilateral transection of the cavernous nerve (CN) for one week. After one-week, animals were orally administered 0, 0.05 or 0.005 mg sildenafil/kg and the erectile response following topical application to the penile shaft of 250mg or 100mg NO-MP, or blank-MP, was monitored over a two-hour timeframe by recording the intracorporal pressure normalized to systemic blood pressure (ICP/BP, N=5 animals/treatment group).Oral treatment with sildenafil by itself resulted in no observable erectile response. However, a combination of orally administered 0.05 sildenafil/kg with topical application of 250mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p-value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 minutes; t-test, p-value = 0.041).Our results demonstrate a synergistic effect between orally administered PDE5i and topically applied NO-MP in eliciting an erectile response. Furthermore, they suggest a potential novel therapeutic approach to treat men with ED resulting from RP, through combination therapy of a topically applied NO-MP and an orally administered PDE5i.

Probucol improves erectile function by regulating endoplasmic reticulum stress in rats with streptozotocin-induced diabetes.

This study was to explore the effect and mechanism of Probucol on STZ-induced erectile dysfunction in diabetic rats. Thirty SD male rats aged 12weeks were given intraperitoneal injection of STZ after fasting for 12hr. Diabetic rats were haphazardly partitioned under two assemblies and administered 0 or 500mg/kg probucol by oral gavage to 12weeks. Control group was intraperitoneally injected with physiological saline, and saline was administered by oral gavage daily. Intracorporeal pressure was used to evaluate erectile function. Levels of proteins were detected using immunohistochemistry and Western blotting. α-SMA and vWF were detected using immunofluorescence staining. After treatment, erectile function in probucol group was significantly improved. Endoplasmic reticulum stress-related proteins were expressed higher in DM group than in sham group, while expression of these proteins decreased significantly in probucol group. However, α-SMA and vWF were expressed at lower levels in DM group than in sham group, and probucol treatment reversed this phenomenon. Finally, Bax and Caspase3 were expressed at higher levels and Bcl-2 was expressed at lower levels in DM group, while the opposite result was obtained in probucol group. In conclusions, probucol improves erectile function by reducing endothelial dysfunction and inhibiting PERK/ATF4/CHOP pathway in STZ-induced diabetic rats.

Good urodynamic practice: Pressure signal quality immediately after catheter insertion for cystometry with a water-filled pressure transducer system and its relevance for the ICS zero procedure.

AimThis study aims to evaluate the intracorporeal pressures immediately after the insertion of the catheters for urodynamic testing with a water‐filled urodynamic pressure transducer system to determine the relevance of the International Continence Society (ICS) zeroing principles.MethodsHere, a retrospective analysis of a random series of urodynamic recordings is performed. The initial pressures, immediately after the insertion of the catheters, have been compared with the pressures after some milliliters of filling and flushing away of the gel, used with insertion, and/or the mucus and debris from the inserted catheters. Differences of initially recorded intravesical and intrarectal pressures from those after flushing and filling are analyzed and associated with the ICS standard practice of zeroing.ResultsStatistically and clinically significant differences between the initial pressures and the pressures after filling and flushing are observed, with nonphysiological initial pressures in 62% of the studies. Some filling (20 ml or more in the bladder) and flushing of the pressure channels resulted in the registration of physiological pressures and synchronous response from both lines on abdominal pressure increases.ConclusionsThe pressure signal quality of a water‐filled urodynamic system immediately after catheter insertion is low with inaccurately displayed pressure values, but it changes to normal after flushing the pressure channels and some filling. Rezeroing of the intracorporeal pressures immediately after catheter insertion for cystometry is the inappropriate correction procedure that misleadingly modifies the false initial pressures, resulting in ongoing unrealistic urodynamic study pressures.

Research on treating atherosclerotic erectile dysfunction by magnetic adipose-derived stem cells

Objective To explore the effect of magnetic adipose-derived stem cells(ADSCs) on treating atherosclerotic erectile dysfunction(ASED). Methods ADSCs were extracted from para-epididymis fat of SD rats aged 2 to 3 months for culture and identification. ADSCs were labeled with the magnetic resonance contrast agent superparamagnetic iron oxide nanoparticles(SPIONs). Meanwhile, the labeling efficiency, as well as effect on cell viability and proliferation was evaluated using Prussian blue, trypan blue staining and MTT method. The paramagnetism of ADSCs after SPIONs labeling was evaluated through the action of the exterior magnetic field. The atherosclerosis rat model was constructed, and ADSCs were injected into the corpus cavernosum afterwards. Intracorporeal pressure(ICP) was determined in the normal group, atherosclerosis group, ADSCs treatment with no action of magnetic field group, and ADSCs treatment with action of exterior magnetic field group after 4 weeks.Contents of smooth muscle and endothelium in corpus cavernosum of rats were detected using immunohistochemical staining. In addition, SOD and NOS activities, as well as MDA content were detected by ELISA. Results ADSCs extracted from para-epididymis fat of rats had grown actively and had high purity. Besides, they showed multi-lineage differentiation. SPIONs could be effectively absorbed by ADSCs, which would not remarkably inhibit the proliferation and cell viability of ADSCs. Iron content in cell was positively correlated with the iron concentration in the labeled SPIONs, and ADSCs showed paramagnetism after SPIONs labeling. ADSCs transplantation could notably improve the erectile function of ASED rats and enhanced the endothelium and smooth muscle contents in corpus cavernosum. Moreover, it could also correct the oxidative stress state in corpus cavernosum tissue, and some ADSCs had differentiated into smooth muscle and endothelial cells. Conclusions ADSCs transplantation can markedly improve the erectile function of ASED rats. Furthermore, magnetic induction has promoted the colonization of ADSCs in the corpus cavernosum, which contributes to enhancing the therapeutic effect of ADSCs and provides a new thinking and concept for stem cell therapy. Key words: Plaque, Atherosclerotic; Erectile Dysfunction; Mesenchymal Stem Cells

High resolution non-invasive intraocular pressure monitoring by use of graphene woven fabrics on contact lens

Monitoring intracorporal pressures are important for health care and diagnosis. In this work, a contact lens tonometer employing graphene woven fabrics (GWFs), which indicate great sensibility of resistance to strain, flexibility, stretchability, transparency, and biocompatibility, is proposed for real-time monitoring intraocular pressure (IOP) with high resolution. The mechanical properties of the device during the deformation were analyzed, and the sensitivity of the fabricated device was tested on a mimic human eyeball. In vitro experiments on porcine eyes were executed to test the effectiveness of the device. The change rate of resistance under different IOP was tested. Also, the relationship between the current changes and IOP variation when keeping the voltage constant for different devices was obtained. The contact lens tonometers with GWFs as high-resolution sensing element have shown a promising prospective to realize the low-cost disposable sensing contact lens with lower power.

Pericardium in Reconstructive Urologic Surgeries: A Systematic Review and Meta-Analysis

Introduction: The use of pericardium has been expanded into different surgical modalities; however, there are scarce data regarding the feasibility of the pericardium in reconstructive urologic surgeries. We systematically reviewed the literature on the effectiveness of the pericardial tissue for reconstructive urologic surgeries. Materials and Methods: PubMed and Scopus were searched online for evidence on the use of the pericardium in urologic surgeries. Through the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, 38 of 4,071 studies were identified. Results: A total of 715 patients and 139 animals underwent reconstructive urologic surgeries using the pericardium. Bladder, urethral, and renal reconstructions were successful in 100% of the human cases. The rates of dissatisfaction, glans hypoesthesia, and penile shortening were comparable between the pericardial graft surgeries and the other operations during penile straightening, but there was a trend among the patients with pericardial grafts toward having a more penile curvature at follow-up (risk ratio [RR] 2.03, 95% CI 0.90–4.61, p = 0.09; I² = 0%). Among the animal studies, there were 4 reports of penile reconstruction, 7 studies of bladder reconstruction, and 1 study of urethroplasty. Bladder reconstruction and urethroplasty were successful in 83 and 20% of the animals, respectively. The pooled result of the stimulated intracorporeal pressure 5 V significantly favored pericardial grafts during penile reconstruction (RR 2.61, 95% CI 1.26–3.97, p = 0.0002; I² = 0%). Conclusions: Our systematic review demonstrates the feasibility of the pericardium, regardless of its type, in urologic surgeries. It, however, seems that urethral substitution needs further investigation. Given the lower cost, easier handling, and less immunogenicity of the pericardium, further studies are required to examine its pros and cons.

Nonhuman primate model of persistent erectile and urinary dysfunction following radical prostatectomy: Feasibility of minimally invasive therapy.

Persistent urinary incontinence (UI) and/or erectile dysfunction (ED) occur in 30-50% of post-radical prostatectomy patients regardless of nerve sparing approaches. Identification of potential treatment options for these patients will require testing in an animal model that develops these chronic conditions. The objective was to characterize a nonhuman primate (NHP) model of persistent post-prostatectomy ED and UI and then test the feasibility of periurethral injection of the chemokine CXCL-12. Ten adult male cynomolgus monkeys were used. Two were used for study of normal male nonhuman primate genitourinary anatomy. Five were used for measures of sexual behavior, peak intra-corporal pressure (ICP), abdominal leak point pressures (ALPP) 3 and 6-months post open radical prostatectomy (ORP). Three additional ORP animals received ultrasound-guided peri-urethral injection of chemokine CXCL12 6 weeks after ORP, and UI/ED evaluated for up to 3 months. The anatomy, innervation, and vascular supply to the prostate and surrounding tissues of these male NHPs are substantially similar to those of human beings. ORP resulted in complete removal of the prostate gland along with both neurovascular bundles and seminal vesicles while permitting stable restoration of vesico-urethral patency. ORP produced sustained (6 months) decreases in ALPP, ICP's, and sexual function. Transurethral injection of chemokine CXCL12 was feasible and had beneficial effects on erectile and urinary function. ORP in NHPs produced persistent erectile and urinary tract dysfunction. Periurethral injection of CXCL-12 was feasible and improved both urinary incontinence and erectile dysfunction and suggests that this model can be used to test new approaches for both conditions.

S-nitrosylation of endothelial nitric oxide synthase impacts erectile function

Neuronal and endothelial nitric oxide synthases (nNOS and eNOS respectively) play major roles in generating the nitric oxide bioactivity necessary for erectile function. S-nitrosylation has been shown to regulate NOS activity. The presence of S-nitrosylated NOS in the penis and the impact of NOS S-nitrosylation/denitrosylation on erectile function were examined. S-nitrosylated forms of NOS were identified by biotin-switch assay followed by western blot analysis. Erectile function in S-nitrosoglutathione reductase deficient (GSNO+/-) and null (GSNO-/-) mice were assessed by continuous cavernous nerve electrical stimulation (CCNES). Glutathione ethyl ester (GSHee) was used to manipulate S-nitrosylated NOS levels. Immunohistological and immunofluorescence analyses were used to identify the location of eNOS and GSNO-R in corporal tissue. eNOS and nNOS were S-nitrosylated in unstimulated penises of the mice. CCNES resulted in a time-dependent increase in eNOS S-nitrosylation with peak eNOS S-nitrosylation observed during detumescence. S-nitrosylated nNOS levels were unchanged. Intracorporal injection of GSHee reduced S-nitrosylated eNOS levels, enhancing time to maximum intracorporal pressure (ICP). eNOS and GSNO-R co-localize to the endothelium of the corpus cavernosum in the mouse and the human. ICP measurements obtained during CCNES demonstrate GSNO-R+/- and GSNO-R-/- animals cannot maintain an elevated ICP. Results suggest eNOS S-nitrosylation/denitrosylation is an important mechanism regulating eNOS activity during erectile function. GSNO-R is a key enzyme involved in the eNOS denitrosylation. The increase in eNOS S-nitrosylation (inactivation) observed with tumescence may begin a cycle leading to detumescence. Clinically this may indicate that alterations in the balance of S-nitrosylation/denitrosylation either directly or indirectly contribute to erectile dysfunction.

Pioglitazone's beneficial effects on erectile function preservation after cavernosal nerve injury in the rat are negated by inhibition of the insulin-like growth factor-1 receptor: a preclinical study.

To determine if the insulin-like growth factor-1 (IGF-1) pathway is involved in the improvement in erectile function recovery in rats after nerve crush injury treated with pioglitazone (Pio). Sprague-Dawley rats were divided into four groups. The first group received sham operation (n = 5). The second group underwent bilateral cavernous nerve injury (BCNI, n = 7). The third group received BCNI and Pio treatment (BCNI + Pio, n = 7), whereas the fourth group underwent BCNI with Pio treatment and IGF-1 inhibition (BCNI + Pio + JB-1, n = 7). The IGF-1 receptor (IGF-1R) was inhibited by JB-1, a small molecular antagonist of the receptor. After 14 days of treatment, erectile function was measured via intracorporal pressure normalized to mean arterial pressure (ICP/MAP) and the major pelvic ganglion and cavernous nerve harvested for western blot and immunohistochemistry (IHC) of phosphorylated-IGF-1Rβ (p-IGF-1Rβ), phosphorylated-ERK1/2 (p-ERK1/2), and neuronal NOS (nNOS). BCNI + Pio animals exhibited improvements in ICP/MAP, similar to Sham animals, and BCNI + Pio + JB-1 rats demonstrated a reduced ICP/MAP similar to BCNI-only rats at all measured voltages. Western blot results showed upregulation of p-IGF-1Rβ was observed in the BCNI + Pio group. Low levels of p-ERK1/2 were seen in the JB-1-treated animals. The immunoblot results were supported by IHC findings. Intense IHC staining of nNOS was detected in the BCNI + Pio group. The group treated with JB-1 showed minimal protein expression of p-ERK1/2, nNOS, and p-IGF-1Rβ. Pio improves erectile function in rats undergoing BCNI via an IGF-1-mediated pathway.

Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes

BackgroundCurcumin, a naturally occurring anti-inflammatory compound, has shown promise in pre-clinical studies to treat erectile dysfunction (ED) associated with type-1 diabetes. However, poor bioavailability following oral administration limits its efficacy. The present study evaluated the potential of topical application of curcumin-loaded nanoparticles (curc-np) to treat ED in a rat model of type-2 diabetes (T2D). AimDetermine if topical application of curc-np treats ED in a T2D rat model and modulates expression of inflammatory markers. MethodsCurc-np (4 mg curcumin) or blank nanoparticles were applied every 2 days for 2 weeks to the shaved abdomen of 20-week-old Zucker diabetic fatty male rats (N = 5 per group). Lean Zucker diabetic fatty male rat controls were treated with blank nanoparticles (N = 5). Penetration of nanoparticles and curcumin release were confirmed by 2-photon fluorescence microscopy and histology. Erectile function was determined by measuring intracorporal pressure (ICP) normalized to systemic blood pressure (ICP/BP) following cavernous nerve stimulation. Corporal tissue was excised and reverse transcription and quantitative polymerase chain reaction used to determine expression of the following markers: nuclear factor (NF)-κβ, NF-κβ-activating protein (Nkap), NF erythroid 2-related factor-2, Kelch-like enoyl-CoA hydratase-associated protein-1, heme oxygenase-1 (HO-1), variable coding sequence-A1, phosphodiesterase-5, endothelial and neuronal nitric oxide synthase, Ras homolog gene family member A, and Rho-associated coiled-coil containing protein kinases-1 and -2. OutcomesErectile function by determination of ICP/BP and expression of molecular markers in corporal tissue by RT-qPCR. ResultsNanoparticles penetrated the abdominal epidermis and persisted in hair follicles for 24 hours. Curc-np-treated animals exhibited higher average ICP/BP than animals treated with blank nanoparticles at all levels of stimulation and this was statistically significant (P < .05) at 0.75 mA. In corporal tissue, Nkap expression decreased 60% and heme oxygenase-1 expression increased 60% in curc-np- compared to blank nanoparticle–treated animals. ICP/BP values inversely correlated with Nkap and directly correlated with HO-1 expression levels. Clinical TranslationThese studies demonstrate the potential for topical application of curc-np as a treatment for ED in T2D patients. ConclusionsThe T2D animal model of ED represents a more prevalent disease than the more commonly studied type-1 diabetes model. Although there is improved erectile response in curc-np-treated animals, only at the lower levels of stimulation (0.75 mA) was this significant compared to the blank nanoparticle–treated animals, suggesting more studies are needed to optimize protocols and evaluate toxicity. Topical application of curc-np to a rat model of T2D can systemically deliver curcumin, treat ED, and modulate corporal expression of inflammatory markers.Draganski A, Tar MT, Villegas G, et al. Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes. J Sex Med 2018;15:645–653.

164 The Effects of Multiple Adipose-Derived Stem Cell Intracorporeal Injections on Erectile Dysfunction in a Rat Model of Cavernosal Nerve Injury

Nerve injury after radical prostatectomy leads to erectile dysfunction in over half of treated patients. Despite contemporary advancements, current therapies are inefficient. Recently, experiments utilizing stem cell therapy have shown promising outcomes. In this study, using a rat model of cavernosal nerve injury (CNI), we sought to discover the effect of intracorporal injection (IC) of adipose-derived stem cells (ADSC) on erectile function (EF). Sprague-Dawly rats were randomized into four groups of rats (n=8/group): 1) EXP-1 group in which the animals underwent laparotomy (Lap) with CNI and IC injection of ADSC at the time of surgery. 2) EXP-2 group in which the rats underwent Lap with CNI and IC injection of ADSC both at the time of surgery and three weeks post CNI. 3) Crush group underwent Lap with CNI, and 4) The Sham control group underwent Lap and immediate closure. Six weeks after CNI, all four groups received EF evaluation via cavernosal nerve stimulation at 2.5V, 5V, and 7.5V and measurement of the intracorporal pressure response. Penile and major pelvic ganglion tissue was harvested for immunohistochemical (IHC) analysis.

MP41-15 STEM CELL ACTIVATION IN THE MAJOR PELVIC GANGLION IS ENHANCED BY STROMAL DERIVED FACTOR-1 PENILE INJECTIONS FOLLOWING NERVE INJURY

You have accessJournal of UrologyStem Cell Research1 Apr 2017MP41-15 STEM CELL ACTIVATION IN THE MAJOR PELVIC GANGLION IS ENHANCED BY STROMAL DERIVED FACTOR-1 PENILE INJECTIONS FOLLOWING NERVE INJURY Nikolai Sopko, Hotaka Matsui, Takahiro Yoshida, Xiaopu Liu, Max Kates, and Trinity Bivalacqua Nikolai SopkoNikolai Sopko More articles by this author , Hotaka MatsuiHotaka Matsui More articles by this author , Takahiro YoshidaTakahiro Yoshida More articles by this author , Xiaopu LiuXiaopu Liu More articles by this author , Max KatesMax Kates More articles by this author , and Trinity BivalacquaTrinity Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1283AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Stem cells are believed to play a role in nerve regeneration following nerve injury. Stromal Derived Factor-1 (SDF1) is potent stem cell chemokine. We investigated whether penile injections with SDF1 following bilateral nerve crush injury (BCNI) can enhance stem cell recruitment and activation in the major pelvic ganglion (MPG). METHODS Sprague Dawley (350g) male rats underwent sham procedure or BCNI (n=10/group). Starting on the day of surgery, BCNI animals received penile injections with 1ug of SDF1 or saline QOD for 5 injections. Sham animals received saline penile injections only. 2 weeks after BCNI, intracorporeal pressure (ICP) response to cavernous nerve stimulation was assessed (n=5/group) and MPGs were collected and RNA was isolated (n=5/group). Stem cell activity in the MPG was assessed using a stem cell expression array expressed as mean fold-change ± SE normalized to sham. RESULTS SDF1 penile injections resulted in improved ICP preservation following BCNI compared to animals receiving saline injections. Sham animals had significantly greater (P<0.05, 1-way ANOVA with Tukey’s post-hoc testing) than BCNI+saline at all voltages (2, 4, 6, 8v), whereas there was no significant difference between Sham and BCNI+SDF1 at any voltages. Additionally, BCNI+SDF1 had greater ICP at 2v and 4v compared to BCNI+saline (0.40±0.09 vs. 0.11±0.08, p<0.05 and 0.47±0.11 vs. 0.12±0.08, p<0.05, respectively). Stem cell-associated gene expression normalized to Shams was globally increased following BCNI and BCNI+SDF1 had a greater increase in expression compared to BCNI+saline (7.89±0.67 fold vs. 1.87±0.15 fold, p<0.0001). On subset analysis, stem cell pathways had significantly greater expression in BCNI+SDF1 compared to BCNI+saline including cytokines and growth factors (6.45±0.63 vs. 1.86±0.13, p<0.0001), Notch pathway (7.72±0.96 vs. 1.95±0.17, p<0.0001), Wnt pathway (7.01±0.68 vs. 1.87±0.12, p<0.0001), mesenchymal stem cell markers (6.33±1.16 vs. 1.82±0.40, p=0.0015), and neural cell lineage markers (6.63±0.51 vs. 1.85±0.14, p=0.0003). CONCLUSIONS SDF1 penile injections improve preservation of erectile function following BCNI and are associated with increased stem cell pathway activation in MPG. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e541 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Nikolai Sopko More articles by this author Hotaka Matsui More articles by this author Takahiro Yoshida More articles by this author Xiaopu Liu More articles by this author Max Kates More articles by this author Trinity Bivalacqua More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP86-09 WATER JET DISSECTION OF THE CAVERNOUS NERVES: A COMPARATIVE STUDY TO BLUNT CAVERNOUS NERVE INJURY IN A RAT MODEL AND ITS IMPLICATION ON ERECTILE FUNCTION

You have accessJournal of UrologySexual Function/Dysfunction: Basic Research & Pathophysiology I1 Apr 2016MP86-09 WATER JET DISSECTION OF THE CAVERNOUS NERVES: A COMPARATIVE STUDY TO BLUNT CAVERNOUS NERVE INJURY IN A RAT MODEL AND ITS IMPLICATION ON ERECTILE FUNCTION Husain Alenezi, Ling X De Young, Gerald Brock, and Stephen E Pautler Husain AleneziHusain Alenezi More articles by this author , Ling X De YoungLing X De Young More articles by this author , Gerald BrockGerald Brock More articles by this author , and Stephen E PautlerStephen E Pautler More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2317AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Postoperative erectile dysfunction (ED) remains a commonly prevalent outcome after radical prostatectomy (RP) despite three decades of evolving surgical techniques and innovative prevention and treatment strategies. Water-jet technology is widely utilized for dissection in neurosurgical procedures due to its minimal effects on the function of nerves. Our objective is to study the impact of water-jet dissection (WJD) of the cavernous nerves (CNs) on postoperative erectile function (EF) and compare it to standard dissection in an established model of blunt surgical trauma of CNs in rats. METHODS Fifteen Sprague-Dawley male rats were randomly divided into two groups; group 1 (WJD) rats were subjected to WJD and barotrauma of bilateral CNs using a fluid pressure of 15 atm (n=8), while group 2 (BT) rats were subjected to standard dissection of the nerves and blunt trauma of bilateral CNs (n=7), in a survival surgery. After 4 weeks, postoperative erectile function was assessed by measuring the intracorporeal pressure (ICP) during 3 electrical stimulations of the CNs under anesthesia. Euthanasia was performed after harvesting the penile tissue for histopathological examination. The peak ICP was noted and the area under the curve (AUC) was calculated for each stimulation. Cross-sections from the penile tissue were prepared and stained with Masson trichrome dye. Digital copies of the slides at x100 and x200 magnifications were obtained and analyzed using image analysis software (Image J) to quantify the fibrosis ratio within each corpora cavernosum. RESULTS Both animal groups had a comparable preoperative weight with a mean of 609.6 ± 99.9 gm and 570.2 ± 72.8 gm in groups WJD and BT, respectively (p= 0.406). WJD rats demonstrated a significantly higher mean peak ICP of 65.7 ± 32.2 cm H2O in comparison to a mean peak ICP of 33.4 ± 23.5 cm H2O in BT (p <0.0001). WJD was also associated with more sustainable rise in the ICP in comparison to BT as the mean AUC was 3425.7 ± 1671 and 2163.2 ± 1551, respectively (p= 0.012). The ratio of fibrosis was comparable between the groups with a mean of 63.7% ± 11.5 vs. 64% ± 7 for x100 magnification (p=0.933), and 68% ± 11.3 vs. 64.6 % ± 8.5 for x200 magnification (p= 0.372) in WJD and BT, respectively. CONCLUSIONS In this study, WJD of the CNs was associated with a significantly better postoperative ICP than blunt trauma. Thus WJD had less of an effect on EF in this rat model of RP. Clinical studies are needed to investigate the effect of WJD on EF in humans post RP. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1109 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Husain Alenezi More articles by this author Ling X De Young More articles by this author Gerald Brock More articles by this author Stephen E Pautler More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...