Intracavernosal Pressure Changes Research Articles

(099) Dual Effect of a Serotonin and Dopamine Reuptake Inhibitor (IP2018), and the Search for a Depressive Rat Model with Erectile Dysfunction

Abstract Introduction In patients with major depressive disorder, up to 68% present with comorbid sexual dysfunction, which resolves in only 5% to 30% of patients treated with antidepressants. Several groups of antidepressants negatively affect sexual function. Objective The present study investigated whether a newly developed amine transport inhibitor, IP2018, improves depression and erectile function in the same dose range. Methods The dose-dependent effect of IP2018 in two different mouse models for depression, the mouse forced swim test (mFST) and mouse tail suspension test (mTST), is reported. In male Wistar, Sprague Dawley and the depressive rats (Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL)), increases in intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured, and the ratio ICP/MAP was used as a measure of erectile function. We investigated whether IP2018 induces changes in ICP or flow and whether IP2018 facilitates suboptimal increases in ICP induced by cavernosal nerve electrical stimulation. The late IP2018 procedure was performed in the rest of the rats to evaluate their erectile function. Results We found that infusion of IP2018 dose-dependently improved mFST and was more potent than citalopram. At the same time, higher doses of IP2018 were required to obtain effect in the mTST model, and IP2018 was equipotent to citalopram. Infusion of low doses of IP2018 dose-dependently increased the number and the duration of spontaneous erections. At the highest dose of IP2018, the increases in the number and duration of spontaneous erections were similar to the effect of the lowest dose, and the increases in flow were 5 times higher. IP2018 (1-30 μM) caused small relaxations in isolated corpus cavernosum strips. FSL and FRL rats showed a diminished ICP/MAP compared to Sprague Dawley control rats. Conclusions IP2018 is more potent or has a similar effect to the well-known antidepressant drug citalopram in mouse models for depression. The potent effect of IP2018 on erectile function in anaesthetized rats suggests that IP2018 in the same dose range has positive effects on both depression and erectile function. FSL/FRL rats appear to allow the study of drug effects on both depression and sexual function in one animal model. Disclosure Yes, this is sponsored by industry/sponsor: Initiator Pharma A/S Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Initiator Pharma A/S

Application of laser speckle blood perfusion imaging in the evaluation of erectile function in rats.

Intracavernosal pressure measurement is the gold standard for evaluating erectile function in experimental animals, but it has the shortcoming of being invasive. This study aimed to explore the application of laser speckle perfusion imaging in evaluating erectile function in rats. Sixty Sprague Dawley rats were randomly divided into the sham operation and model groups (n=30 each). A rat model of neuroinjury erectile dysfunction was established by surgically damaging the bilateral cavernous nerves in the model group. Simulated surgery was performed in the sham operation group; the nerves were not damaged. Erectile function was evaluated by comparing the changes in intracavernosal pressure and blood flow fluctuations when the cavernous nerve was stimulated using the same voltage parameters. Intracavernosal pressure in the model group was significantly lower than that in the other group when using 2.5V. No significant difference was found in cavernous blood flow fluctuation between the two groups when using 0.5V. Cavernous blood flow fluctuation in the model group after 2.5V, 5V and 7.5V stimulations was significantly lower than that in the sham operation group. Evaluating erectile function in rats is feasible by measuring the cavernous blood flow using laser speckle perfusion imaging.

HP-1-6 Dual Effect of the Serotonin and Dopamine Reuptake Inhibitor, IP2018 on Depression and Erectile Function in Rats

The present study investigated whether a newly developed amine transport inhibitor, IP2018, improves depression and erectile function in the same dose range. The dose-dependent effect of IP2018 in two different mouse models for depression the mouse forced swim test (mFST) and mouse tail suspension test (mTST) is reported. In male Wistar rats increases in intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured and the ratio ICP/MAP used as a measure of erectile function. It was investigated whether IP2018 induces changes in ICP and whether IP2018 facilitate suboptimal increases in ICP induced by cavernosal nerve electrical stimulation. Infusion of IP2018 dose-dependently improved mFST and was more potent than cipramil, while higher doses of IP2018 were required to obtain effect in the mTST model and IP2018 was equipotent to cipramil. Infusion of low doses of IP2018 dose-dependently increased the number and the duration of spontaneous erections. At the highest dose of IP2018 infused, the increases in number and duration of spontaneous erections were similar to the effect of the lowest. The occurrence and the magnitude of spontaneous erectile responses after infusion of 1 mg/kg IP2018 were larger in 6 weeks-old versus 12-13 week old rats. Suboptimal stimulation of the cavernous nerve induced reproducible increases in ICP/MAP that were unchanged in the presence of IP2018. IP2018 (1-30 μM) only caused small relaxations in isolated corpus cavernosum strips.

9‐Hydroxycanthin‐6‐One Induces Penile Erection and Delays Ejaculation

Eurycoma longifolia Jack (Simaroubaceae) has the reputation as a male aphrodisiac because it is claimed to increase virility and sexual prowess. Nevertheless, whether or not E. longifolia regulates directly the muscle tone of corpus cavernosa and/or seminal vesicle (SV) remains unclear. Even until now, the compositions that could account for its aphrodisiac property are still unknown We examined the effect of 9-hydroxycanthin-6-one (9-HC-6-one), a β-carboline alkaloid isolated from E. longifolia, on penile erection and ejaculation, and further elucidated the mechanism of action. 9-HC-6-one induces penile erection and delays ejaculation. Drug's effect was studied on rat corpus cavernosum (CC) and SV in vitro, and on the changes in intracavernosal pressure (ICP) after IC injection and intraluminal pressure (ILP) of the SV after hypogastric nerve stimulation (HNS), respectively. 9-HC-6-one relaxed significantly phenylephrine (PE)-precontracted CC. Such response was not attenuated by endothelium disruption, N(G) -nitro-L-arginine methyl ester, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one treatment, suggesting that a nitric oxide/cyclic guanosine monophosphate-dependent pathway was precluded. 9-HC-6-one attenuated PE-induced contraction by blocking cell surface and internal calcium channels with a higher potency for internal calcium release. This compound also antagonized calcium-evoked contraction in Ca2+ -free, high K+ -depolarizing condition, suggesting that interfering with the entry of calcium through voltage-dependent channels also contributed to 9-HC-6-one-induced corporal relaxation. After IC application of 9-HC-6-one, a significant rise in ICP was observed as compared with the application of normal saline. 9-HC-6-one relaxed significantly norepinephrine (NE)- and KCl-precontracted SV, and antagonized NE-induced oscillatory contraction as potent as clomipramine. Finally, the HNS-evoked increase in ILP was dose-dependently repressed after challenge by 9-HC-6-one. 9-HC-6-one might be the active component that contributed to the aphrodisiac effect of E. longifolia by antagonizing the smooth muscle tone of CC as well as SV probably through interfering with Ca2+ mobilization.

FK506 Neuroprotection After Cavernous Nerve Injury is Mediated by Thioredoxin and Glutathione Redox Systems

Immunophilin ligands such as FK506 (FK) preserve erectile function (EF) following cavernous nerve injury (CNI), although the precise mechanisms are unclear. We examined whether the thioredoxin (Trx) and glutathione (GSH) redox systems mediate this effect after CNI. To investigate the roles of Trx reductase 2 (TrxR2) and S-Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI. Adult male rats, wild-type (WT) mice, and GSNOR deficient (GSNOR -/-) mice were divided into four groups: sham surgery (CN [cavernous nerves] exposure only) + vehicle; sham surgery + FK (5 mg/kg/day/rat or 2 mg/kg/day/mouse, for 2 days, subcutaneous); CNI + vehicle; and CNI + FK. At day 4 after injury, electrically stimulated changes in intracavernosal pressure (ICP) were measured. Penises were collected for Western blot analysis of TrxR2, GSNOR, and Bcl-2, and for immunolocalization of TrxR2 and GSNOR. EF assessment represented by maximal ICP and total ICP in response to electrical stimulation. Evaluation of protein expression levels and distribution patterns of antioxidative/nitrosative and antiapoptotic factors in penile tissue. EF decreased after CNI compared with sham surgery values in both rats (P < 0.01) and WT and GSNOR -/- mice (P < 0.05). FK treatment preserved EF after CNI compared with vehicle treatment in rats (P < 0.01) and WT mice (P < 0.05) but not in GSNOR -/- mice. In rats, GSNOR (P < 0.01) and Bcl-2 (P < 0.05) expressions were significantly decreased after CNI. FK treatment in CN-injured rats restored expression of GSNOR and upregulated TrxR2 (P < 0.001) and Bcl-2 (P < 0.001) expressions compared with vehicle treatment. Localizations of proteins in the penis were observed for TrxR2 (endothelium, smooth muscle) and for GSNOR (nerves, endothelium, smooth muscle). The neuroprotective effect of FK in preserving EF after CNI involves antioxidative/nitrosative and antiapoptotic mechanisms mediated, to some extent, by Trx and GSH systems.

Classification of the distribution of cavernous nerve fibers around the prostate by intraoperative electrical stimulation during laparoscopic radical prostatectomy

We investigated the distribution of cavernous nerve (CN) fibers around the prostate by electrical nerve stimulation during laparoscopic radical prostatectomy to classify the distribution of the CN fibers. Electrical stimulation was performed on 30 consecutive patients with localized prostate cancer; middle of the neurovascular bundle (NVB, point A), base of the NVB (point B), the rectal wall 1 cm posterolateral to the NVB (point C) and the lateral aspect of the prostate (point D). We measured the intraurethral pressure at the midportion to detect the changes in intracavernosal pressure. The mean maximum changes were 10.5 ± 7.9, 11.6 ± 8.8, 9.6 ± 7.4 and 6.7 ± 7.0 cm H(2)O at points A, B, C and D, respectively. The patterns of CN fiber distribution were divided into four groups: type 1 (23%), the bundle corresponding to the NVB; type 2 (7%), the bundle from the rectal wall to the prostate; type 3 (27%), the plate including NVB and posterolateral to NVB; and type 4 (43%), the plate between the rectal wall posterolateral to the NVB and the lateral aspect of the prostate. Distribution of the CNs in a bundle-like formation was considered to account for 30%, whereas a plate-like formation accounted for 70%. Understanding these four patterns of CN fiber distribution should facilitate accurate CN-sparing radical prostatectomy.

Peripheral Modulation of Dopaminergic Receptors Affects Erectile Responses in Rats

Clinical observations have suggested that dopaminergic mechanisms are involved in the regulation of male sexual responses, including erection. Apomorphine was initially reported to exert its erectogenic effects by modifying central dopaminergic activity. This study aimed primarily at evaluating and investigating the effect of apomorphine on erectile functions in rats and its potential effects on the cardiovascular system, as well as the possible role of dopaminergic stimulation in the peripheral control of erection. Measurement of intracavernosal pressure changes elicited by electrical stimulation of the cavernosal nerve in anaesthetized rats and mating tests were used. SCH23390, the D1 receptor antagonist, attenuated penile response to electrical stimulation. Intravenous administration of apomorphine in low dose (100 microg/kg), but not in high dose, significantly potentiated erectile responses to electrical stimulation. Intracavernosally injected apomorphine (50 microg/kg) significantly potentiated the filling rate of the corpora cavernosa 5 min. after injection, and did not induce erection in absence of electrical stimulation. In addition, apomorphine amplified the male sexual and copulatory behaviour by reducing ejaculation, mount and intromission latencies, and significantly increasing the number of ejaculations per session. However, apomorphine produced rapid and long-lasting hypotension and potentiated the hypotension and tachycardia associated with nerve-stimulated penile erection. Our results suggest that D1-dopaminergic receptors may be functionally involved in the peripheral mediation of penile erection. Apomorphine may amplify sexual and copulatory behaviour and may also, by a complementary role, amplify neurogenically mediated erections by acting in the periphery.

Increased Intracavernosal Pressure Response in Hypertensive Rats After Chronic Hemin Treatment

Erectile dysfunction (ED) is increased in prevalence in patients with arterial hypertension. Whether upregulation of heme oxygenase (HO) expression could improve penile erection has been unknown. To correlate altered expression profiles of HO-1 and soluble guanylyl cyclase (sGC) in penile tissues with low intracavernosal pressure (ICP) in adult spontaneously hypertensive rats (SHR); and to investigate therapeutic effect of hemin-induced upregulation of HO-1 in penile tissues on ED developed in adult SHR. Intracavernosal pressure changes after electrical stimulation were monitored in adult SHR and age-matched normotensive Sprague-Dawley (SD) rats after chronic administration of either hemin or hydralazine. Expression levels of HO-1, HO-2, sGC, and phosphodiesterase type 5 (PDE5) were examined with Western blot. Frequency-dependent ICP changes were reduced in adult SHR. Three weeks after hemin treatment, high blood pressure of SHR was normalized and ICP responses to electrical stimulations in SHR were significantly increased to the level of normotensive rats. Hydralazine-treated SHR had normalized blood pressure but unaltered low ICP response. Expression of HO-1 and sGC was upregulated and that of PDE5 downregulated in hemin-treated, but not hydralazine-treated, SHR. Decreased erectile responses in adult SHR can be improved through chronic hemin treatment. Prolonged upregulation of HO-1 and sGC as well as lowered expression of PDE5 may at least partially explain the effect of hemin treatment on ICP. Upregulation of HO-1 may represent a novel therapeutic approach to treat ED.

State of knowledge in structural mechanics of penile erection, and some areas of ignorance

4108 Citation: Journal of Biomechanics 2006; Vol. 39 Suppl. 1, page S345 State of knowledge in structural mechanics of penile erection, and some areas of ignorance A. Gefen1, J. Chen2, D. Elad1 1 Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel 2 Department of Urology, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel Penile rigidity is determined by geometrical properties, intracavernosal pressure (ICP), tissue mechanical properties and interactions between these factors. Here we review the points of strength and of weakness in the state of knowledge regarding each factor. Geometrical properties: Ultrasound is now in routine clinical use for evaluating the anatomy of the flaccid and erect penis, and can demonstrate expandability of corpora during erection, their level of symmetry, and the thickness and integrity of the tunica albuginea. MRI was also utilized in basic research and clinical studies of erection, and is able to visualize finer details such as lesions and tears in the tunica and corpora. Both ultrasound and MRI allow for subject-specific structural modeling of the penis, and are particularly suitable for producing three-dimensional finite element (FE) models. Intracavernosal pressure: ICP was measured in normals and erectile dysfunction patients by inserting a catheter instrumented with a pressure transducer to the corpus cavernosum. In animal models (mostly mice, rats and rabbits), the dependence of ICP on dose and frequency of administration of vasodilators had been characterized. ICP changes were reported to occur with age, diseases (diabetes and Peyronie's), and radiation therapy of prostate cancer. It is also known that ICP relates to the buckling force resistance of the penis. From a biomechanical standpoint, experimental data on ICP and its time course of build-up during erection, as well as data on influence of age, disease, and pharmaceutical drugs are essential for setting boundary conditions in FE models. Tissue mechanical properties: This factor is by far less studied than those discussed previously. The organized structure of collagen in the tunica the most important load-bearing structure suggests that it is a highly anisotropic material. The large tissue deformations which occur in the penis during erection also require a constitutive law suitable for large deformation analysis. Since the rigidity phase of erection lasts several minutes, during which soft penile tissues may undergo viscoelastic creep, it is also necessary to characterize the long-term creep modulus of the tunica. Similar experimental data and constitutive modeling are required for the corpus cavernosal tissue.

Feline penile erection induced by topical glans penis application of combination alprostadil and SEPA (Topiglan).

The objective of this study was to evaluate the efficacy of topically applied prostaglandin E1 (PGE(1))+5% SEPA (soft enhancement of percutaneous absorption) on the glans penis in a feline erection model. Erectile response after glans penis administration of PGE(1)+5% SEPA cream (Topiglan, MacroChem Co., Lexington, MA, USA) was compared to the erectile response after intracavernosal administration of the triple-drug combination (1.65 mg papaverine, 25 microg phentolamine, and 0.5 microg PGE(1)). The placebo cream and increasing concentrations (0.25%, 2.5 mg/ml; 0.5%, 5 mg/ml; and 1%, 10 mg/ml) of PGE(1)+5% SEPA were applied in a total volume of 0.1 ml via a plastic needle-less syringe. The control triple-drug combination was administrated intracavernosally via a 30-gauge needle at the completion of each experiment to serve as a control reference. With each application of placebo, PGE(1)+SEPA, and the triple-drug combination, changes in intracavernosal pressure and systemic blood pressure were continuously monitored. Topical application of PGE(1)+SEPA induced increases in intracavernosal pressure in a dose-dependent manner, with minimal effects on systemic blood pressure. The increases obtained with 1% PGE(1) Topiglan cream were similar to the intracavernosal pressure values elicited by the standard intracavernosal triple-drug combination. These data demonstrate that topical glans penis application of PGE(1)+SEPA can induce an erectile response in cats with minimal systemic adverse effects. Oral pharmacological agents are the first-line treatment for male ED. Studies investigating the effectiveness of noninvasive modalities such as topical therapy should continue, because these agents have the potential to avoid the systemic effects commonly seen with oral therapies. Additionally, topical therapy may also benefit patients who are unresponsive to oral agents or have explicit contraindications. Topical PGE(1) application to the glans penis may become an important treatment option in selected patients suffering from erectile dysfunction.

Protective role of the glans penis during coitus.

To examine the hypothesis that the glans penis acts protectively, absorbing forces, during coitus. Five potent patients (mean age 46.8+/-9.7 y), who had indication for surgical excision of the glans for penile carcinoma were included in the present study. Intraoperatively, intracavernosal pressure (ICP) was adjusted by saline infusion and maintained by a pressure feedback infusion pump to a pressure value of 70 mmHg. Using a dynamometer, an external compressive force of 0.5 kg was applied at the glans penis and the changes in ICP were monitored. Measurements were repeated after surgical excision of the glans. Significant ICP changes were noticed in all patients after excision of the glans. Mean preoperative ICP was 161+/-11.5 mmHg, while after glansectomy it reached 206.6+/-13 mmHg. DeltaICP was 45.8+/-10.57 mmHg. Two of the patients' partners reported pain during intercourse postoperatively, possibly due to the impact of the force applied by the rigid corpora cavernosa on the anterior vaginal wall without any absorption by the glans. The glans penis restricts the increase in ICP during sexual intercourse, playing a protective role for both the corpora cavernosa and the female genitalia.

Intracavernosal pressure monitoring in mice: responses to electrical stimulation of the cavernous nerve and to intracavernosal drug administration.

With the development of transgenic mice to evaluate mechanisms of erectile function, it appears particularly advantageous to develop a standardized mouse model of penile erection. The purpose of the study reported here was to evaluate the novel application of intracavernosal pressure (ICP) monitoring in the mouse during electrophysiologic and pharmacologic induction of penile erection. In anesthetized adult male mice, the cavernous nerves (CN) were isolated unilaterally, and the corpora cavernosa were exposed. A 24-gauge angiocath (intravenous catheter) was inserted into the right corpus cavernosum to monitor the ICP, and a 30.5-gauge needle was inserted into the left corpus cavernosum for intracavernosal drug administration. ICP was recorded during CN-stimulated or pharmacostimulated erections. Electrical stimulation of the CN significantly increased the ICP (from 10.09 +/- 2.01 to 34.62 +/- 2.71 mm Hg, P < .05), which then returned to baseline pressure after termination of the electrical stimulation. Pretreatment with intracavernosal administration of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (0.1 mg), inhibited the electrical stimulation-induced changes in ICP (7.17 +/- 1.46 vs 10.38 +/- 2.17 mm Hg, not significant [NS]). Also, intracavernosal administration of papaverine (0.4 mg) produced a significant increase in ICP (from 8.51 +/- 0.69 to 26.37 +/- 5.7 mm Hg, P < .05). We concluded that this technique might be applied to perform quantitative erection physiologic experiments with the mouse as an economical and experimentally advantageous animal model, particularly with the development of transgenic mice to evaluate mechanisms of erectile function.

Feline penile erection induced by transurethral administration of sodium nitroprusside

Nitric oxide (NO) is an important mediator in the relaxation of cavernosal smooth muscle. The aim of this study was to investigate the in vivo feline erectile response after transurethral administration of sodium nitroprusside (SNP), a NO donor drug. Erectile responses after administration of transurethral SNP were compared with those elicited by an intracavernosal control triple-drug combination (1.65 mg papaverine, 25 microg phentolamine, and 0.5 microg prostaglandin E1). SNP was administered via a 20-gauge Jelco intravenous catheter in a volume of 200 microl and changes in intracavernosal pressure, penile length, and systemic blood pressure were monitored. The control triple-drug combination was administered via a 30-gauge needle at the end of each experiment to serve as a control reference. Transurethral administration of SNP (1-4 mg) induced penile erection in a dose-dependent manner with minimal changes in systemic blood pressure. The maximum increase in intracavernosal pressure and penile length after transurethral administration of SNP (4 mg) was significantly less than after the intracavernosal injection of the control triple-drug combination (P<0.01). These data suggest that transurethral administration of SNP can induce an erectile response in cats with minimal side effects.

A Hydrodynamic Model of Rabbit Corpus cavernosum Pressure Responses to Vasodilators

The intracavernosal pressure changes induced by 3 vasodilating drugs, diazoxide, glyceryltrinitrate and verapamil were investigated during autologous extracorporeal penile blood perfusion in an experimental rabbit model. In order to separate the arterial and venous components the experiments were performed with both intact and interrupted penile arterial inflow. The major hemodynamic effect of these drugs was an increased outflow resistance from the corpora cavernosa, probably effected through relaxation of the corporal smooth muscle. However, the intracorporeal pressure responses only reflected a part of the drug-induced smooth muscle relaxation. A theory is presented, according to which the corpora cavernosa are 'accumulating' smooth muscle relaxation, without direct reflection in an increased cavernosal pressure. At the moment when sufficient smooth muscle relaxation is achieved, a sudden increase in cavernosal pressure will appear and lead to an erection. This concept was generated through an approximation of corpora cavernosa to an elastic cylinder following the elastic law of Laplace in combination with the hydrodynamic law of Poiseuilles.