Intracorporeal Pressure Research Articles

Effect of endothelial cell-based iNOS gene transfer on cavernosal eNOS expression and mouse erectile responses

Inducible nitric oxide synthase (iNOS) gene transfer is reported to augment erectile responses in rats, although it is also shown to impair vasorelaxation in cerebral arteries. We investigated the effect of endothelial cell-based iNOS gene transfer on endothelial NOS (eNOS) expression and mouse erectile responses. Human coronary artery endothelial cells (EC) transduced with empty vector (control) or iNOS were grown in culture and transplanted into the corpus cavernosum of severe combined immunodeficient mice. Endothelial NOS expression was compared in control and iNOS-transduced cells grown in the presence or absence of a selective iNOS inhibitor, L-N6- (1-iminoethyl) lysine hydrochloride (L-NIL). At 3-5 days after cell transplantation, we recorded intracorporal pressure (ICP) responses to cavernosal nerve stimulation and measured cavernosal total NO and eNOS protein expression. In this study, EC transduced with iNOS produced significantly more NO than controls but exhibited a twofold downregulation of eNOS protein and mRNA. This effect was reversed by L-NIL. In vivo, the cell-based gene transfer of iNOS led to significantly increased ICP responses, compared to mice transplanted with control ECs. Consistent with the in vitro data, cavernosal lysates had significantly reduced eNOS expression. In conclusion, EC gene transfer of iNOS downregulates EC expression of eNOS by an NOS-dependent mechanism. In the cavernosum of mice transplanted with Inos-transduced EC, nerve-stimulated erectile responses were augmented by the short-term gene transfer. However, our findings suggest that iNOS gene transfer may have deleterious effects on endothelial function if used as a treatment for erectile dysfunction.

ROLE OF TUNICA ALBUGINEA IN ERECTION: IS IT A DYNAMIC OR A STATIC ROLE?

The tunica albuginea (TA) of the penis is claimed to share in erectile mechanism by compressing the emissary veins passing through it. Apparently this claim is theoretical as no experimental studies could be traced in literature proving this concept. We investigated the hypothesis that TA acts as a cover to corpora cavernosa (CC) and spongiosa (CS) and does not have an active role in erectile mechanism. Penises of 9 dogs were degloved and TA was divided at upper, middle and lower 1/3 of the penis. The intracorporal and glans penis (GP) pressures were measured in the TA-covered and non-covered parts of CC and CS in the flaccid and erectile phases. Sham operation, without performing the TA incisions, was done in 7 control animals. In the test animals, intracorporal pressure (ICP) in the non-TA covered corpora and in GP recorded in flaccid phase a mean of 12.2 +/- 0.8 cmH2O for CC and 11.3 +/- 0.7 cmH2O for the CS and GP, and in the erectile phase 98.4 +/- 8.6 and 76.2 +/- 9.3 cmH2O, respectively. There was no significant difference between covered and non-covered corpora or between test and control animals. In conclusion, the TA seems to act as a cover to the corporal tissue. Its absence did not change ICP.

Tunica albuginea overlapping: a novel technique for the treatment of erectile dysfunction

Tunica albuginea (TA) in venogenic erectile dysfunction (VED) was found subluxated and flabby because of degeneration and atrophy of its collagen fibres. This had apparently led to derangement of TA veno-occlusive mechanism. We investigated the hypothesis that overlapping of the subluxated and flabby TA would achieve a competent veno-occlusive mechanism during erection. Tunical overlapping was performed in nine VED patients (age 35.6 +/- 1.6 years). Intracorporal pressure (ICP) was measured pre- and postoperatively. After penile degloving, TA on lateral penile aspect was divided along whole length of corpus cavernosum (CC) and tunical double-breasting for 1-1 1/2 cm was performed. A biopsy was taken from TA and stained with haematoxylin and eosin and Masson's trichrome. Clinical efficiency of the operation was evaluated after 6 months. ICP increased (P < 0.01) postoperatively in the nine patients. The increase was maintained during follow-up period in eight patients and decreased to preoperative level in one. Six months after operation, the eight patients had significantly (P < 0.01) improved scores for the erectile function domain over the preoperative scores. Microscopic examination of TA biopsies showed atrophy of the collagen fibres. Tunical overlapping aims at correction of TA flabbiness, corporal tissue support and improving of veno-occlusive mechanism.

IMPROVING ERECTILE FUNCTION BY SILENCING PHOSPHODIESTERASE-5

We investigated whether phosphodiesterase-5 (PDE5) can be down-regulated by a specific small interfering RNA (siRNA) and whether this would improve erectile function. A PDE5 siRNA encoding oligonucleotide was inserted into pSUPER-retro vector, resulting in the siRNA expressing construct, pPDE5-silencer. The construct was packaged into oncoretroviral particles and then transduced into rat cavernous smooth muscle cells (CSMCs). Cells were examined for PDE5 expression by reverse transcriptase-polymerase chain reaction, Western blotting and immunofluorescence microscopy. Cells were then treated with 10 microM sodium nitroprusside (SNP) and examined for cyclic guanosine monophosphate (cGMP) at 0, 10, 30, 60 and 240 minutes. The siRNA expressing cassette was transferred from the oncoretrovirus to lentivirus, which was then injected into rat penises. Three months later erectile function was examined by electrostimulation and PDE5 expression in cavernous smooth muscle was determined by immunohistochemistry. CSMCs transfected with pPDE5-silencer (CSMC plus siRNA) showed an 88.2% decrease in PDE5 compared with CSMCs transfected with control vector (CSMCs plus vector). Within 10 minutes of SNP treatment cells (CSMCs, CSMCs plus vector and CSMCs plus siRNA) showed similar sharp increases in cGMP. However, while cGMP levels in CSMCs and CSMCs plus vector returned to almost baseline in 1 hour, the cGMP level in CSMCs plus siRNA remained high even 4 hours after SNP treatment. Rats injected with the siRNA expressing lentivirus showed increased electrostimulated erectile function, as measured by peak intracorporeal pressure and the intracorporeal pressure increase, compared with rats injected with control lentivirus. PDE5 expression was decreased in the siRNA treated cavernous smooth muscle. PDE5 expression could be decreased by siRNA, resulting in prolonged cGMP accumulation and improved erection.

INTRAOPERATIVE ELECTROPHYSIOLOGICAL CONFIRMATION OF URINARY CONTINENCE AFTER RADICAL PROSTATECTOMY

To determine the actual effect of nerve sparing radical retropubic prostatectomy (RP) on postoperative urinary continence we used intraoperative electrophysiological testing to confirm functional preservation of the neurovascular bundle (NVB). A total of 85 patients undergoing RP for localized prostate cancer were studied. During RP NVB preservation was assessed macroanatomically. Electrophysiological testing was then performed to confirm NVB preservation. The NVB was electrostimulated and responses were observed by monitoring intracavernous or intraurethral pressure changes. All patients were classified into 3 groups according to the degree of nerve sparing, that is a bilateral nerve sparing group, a unilateral nerve sparing group and a nonnerve sparing group, based on macroanatomical assessment as well as on electrophysiological assessment. Postoperative continence in each group was then determined. Urinary continence at baseline, and 3 and 6 months postoperatively was studied using a self-administered questionnaire. With electrophysiological assessment 20.6% of macroanatomically determined NVB preservations were reclassified. Analysis of the data on groups classified accurately by electrophysiological testing showed that the bilateral nerve sparing group maintained postoperative urinary function significantly more than the unilateral nerve sparing and nonnerve sparing groups. However, when only macroanatomical assessment was considered, no significant difference among the groups was found in urinary function. Electrophysiological assessment revealed that bilateral NVB preservation contributes to early recovery of urinary continence after RP. Thus, intraoperative electrophysiological assessment is useful for predicting postoperative quality of life.

38-Year-Old Man With Priapism and a History of Paranoid Schizophrenia

38-Year-Old Man With Priapism and a History of Paranoid Schizophrenia

Congruence between veno-occlusive parameters during dynamic infusion cavernosometry: assessing the need for cavernosography.

While dynamic infusion cavernosometry (DIC) is being performed with increasing rarity, some centers continue to use this investigation modality. Cavernosography may be utilized to identify the location of patent venous channels in men with venous leak. In an era when venous ligation surgery is being performed with less frequency, the role of cavernosography has been questioned. This study was conducted to define the congruence between the three parameters (flow-to-maintain (FTM), pressure decay (PD) and cavernosography) used in the diagnosis of venous leak during DIC. Established values for the three parameters were utilized and the diagnosis of venous leak was based upon the FTM measurement. All studies were performed using a vasoactive agent-redosing schedule. Cavernosography was conducted using a nonionic contrast agent at an intracorporal pressure of 90 mmHg. In patients with an elevated FTM value, 24% had a normal PD recorded, all of whom had FTM values <10 ml/min. The Pearson correlation coefficient for the relationship between FTM and PD was 0.58 (P=0.025). In all, 36 patients (54%) had an abnormal cavernosogram (CG). All patients who had positive findings on CG had elevated FTM values. On the other hand, 46% of patients with abnormal FTM values had a normal CG. This analysis indicates that almost one-half of men with venous leak diagnosed at the time of DIC based on FTM measurement will fail to have any veins visualized on cavernosography. These data further undermine the value of cavernosography, particularly in men with low-grade venous leak.

The Successful Long-Term Treatment of Age Related Erectile Dysfunction with hSlo cDNA in Rats In Vivo

We have previously reported that 1 intracorporeal injection of 100 microg hSlo/pcDNA reversed the effect of aging on erectile function in a rat model in vivo for at least 2 months. We report our further investigations of the amplitude, duration and physiological relevance of this novel gene transfer approach. A total of 191 retired breeder Sprague-Dawley rats were given a single intracavernous injection of phosphate buffered saline, 1,000 microg pcDNA, or 10, 100 or 1,000 microg pcDNA/hSlo. The animals were studied 1 to 6 months after injection. The intracorporeal pressure (ICP) response to cavernous nerve stimulation and immunostaining as well as hematoxylin and eosin staining were done to evaluate effector nerve integrity and tissue histology, respectively. Gene transfer prevented an age related decrease in resting ICP and a physiologically relevant, significant effect on normalizing erection in vivo, as determined by submaximal (0.5 mA) and maximal (4.0 mA) cavernous nerve stimulation. The effects were observed 1 month after transfection and sustained for 6 months at the 100 and 1,000 microg doses of pcDNA/hSlo (p <0.026). The physiological manifestations of gene transfer were detected as an amelioration of the age related decrease in resting ICP, and parallel increase in the magnitude of the cavernous nerve stimulated an ICP response to a level at which visible erections were again observed in this rat model of aging in vivo.

MT-II induces penile erection via brain and spinal mechanisms.

alpha-Melanocyte-stimulating hormone induces penile erection via melanocortin (MC) receptors in areas surrounding the third ventricle, but spinal and peripheral mechanisms have not been demonstrated. We used pharmacological strategies to localize the site of the proerectile action of the melanocortin receptor agonist MT-II. We administered MT-II intracerebroventribularly (i.c.v.), intrathecally (i.th.), and intravenously (i.v.) and scored penile erection and yawning for 90 min in awake male rats. In some animals i.c.v. or i.th. SHU-9119 was injected 10 minutes before i.c.v. and i.th. MT-II to confirm the MC receptor action of the agonist and to distinguish spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intracorporal pressure responses to intracavernosal injection of MT-II in the anesthetized rat. MT-II induced penile erections in a dose-dependent fashion, with optimal response at 1 microg for both i.c.v. and i.th. routes. Supraspinal MT-II-induced erections were completely suppressed by 1 microg SHU-9119 i.c.v. Yawning was observed with i.c.v. and i.v. MT-II, whereas spinal injection did not produce this behavior. SHU-9119 blocked the erectile responses to i.th. MT-II when injected i.th. but not i.c.v. Intracavernosal MT-II neither increased intracorporal pressure nor augmented neurostimulated erectile responses. The lumbosacral spinal cord contains MC receptors that can initiate penile erection independent of higher centers. We confirmed the supraspinal proerectile action of MT-II. These results provide insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction.

Intraoperative electrical stimulation of cavernous nerves with monitoring of intracorporeal pressure to confirm nerve sparing during radical prostatectomy: Early clinical results.

We performed intraoperative cavernous nerve stimulation with an intracavernous pressure (ICP) monitoring system to confirm nerve sparing during radical pelvic surgery and assessed the results. Nineteen cases of radical prostatectomy and three of radical cystoprostatectomy were examined. Electrical stimulation of the site where the neurovascular bundle (NVB) was determined to run was performed and changes in ICP were measured before and after prostate removal. Of the 22 patients, bilateral NVBs were preserved in six patients while unilateral NVB was preserved in 16. Before dissection, all NVBs examined exhibited positive responses (ICP changes of>5 mmHg) to nerve stimulation. After removal of the prostate, positive responses were observed in 22 (79%) of 28 macroanatomically preserved NVBs. Of 16 sides on which the NVB was not preserved, there were positive responses in five (31%). In these patients, some nerve fibers were macroscopically observed lateral to the original site of NVB. Finally, bilateral or unilateral nerve sparing was confirmed electrophysiologically in 20 (91%) of the 22 patients. Intraoperative stimulation of the NVB while monitoring ICP changes is a simple and reliable method of accurately evaluating the preservation of cavernous nerves. This system may provide further insight into the mechanism of postoperative erectile dysfunction.

Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum.

The etiologies of erectile dysfunction (ED) after nerve-sparing radical prostatectomy have not been clearly elucidated. The aim of this study was to evaluate the effects of cavernous nerve injury on cavernous fibrosis, and to consider measures to prevent irreversible damage to the cavernous tissues. Twenty male Sprague-Dawley rats constituted the study population. The animals were divided into 2 groups; group 1 consisted of sham-operated rats (n = 10), and group 2 consisted of rats that underwent incision of both cavernous nerves (n = 10). Three months later, all rats underwent intracavernous papaverine injection (300 and 600 mg), and intracorporal pressures were recorded. Transforming growth factor-beta(1) (TGF-beta(1)) messenger RNA (mRNA) expression from rat penile tissue was measured using reverse transcriptase-polymerase chain reaction. Hypoxia-inducible factor-1alpha (HIF-1alpha), TGF-beta(1), and collagen I and III protein expressions were determined by Western blot analysis and immunohistochemical staining. Erectile function as studied with intracavernosal papaverine injection and histological analysis of penile cross-sections at 3 months was similar in both groups. TGF-beta(1) mRNA expression, HIF-1alpha, TGF-beta(1), and collagen I and III protein expressions were significantly greater in the neurotomy group. Immunohistochemical staining for TGF-beta(1), HIF-1alpha, and collagen III were qualitatively more positive in the neurotomy group, whereas collagen I staining was similar. This study demonstrates an increase in TGF-beta(1), HIF-1alpha, and collagen III synthesis in rat cavernosal smooth musculature after cavernous neurotomies. In theory, cavernous fibrosis may be reduced by employing various vasoactive agents or interventions that increase oxygenation to the corporal tissues during the postoperative period.

Intracavernosal injection of vascular endothelial growth factor induces nitric oxide synthase isoforms.

To identify genes that are affected by vascular endothelial growth factor (VEGF), as an intracavernosal injection with VEGF improved the recovery of erectile function in a rat model of arteriogenic impotence, specifically examining the three nitric oxide synthase (NOS) genes, nNOS, eNOS, and iNOS. Male rats had their pudendal arteries ligated or underwent a sham operation. They were then treated by an intracavernosal injection with 4 microg of VEGF in phosphate-buffered saline (PBS) or PBS alone. At 6 and 24 h after treatment electrostimulation was applied to the cavernosal nerve and the intracorporal pressure measured. The erectile tissue was then harvested for RNA isolation and cryo-sectioning. The isolated RNA was used for microarray and reverse transcription-polymerase chain reaction (RT-PCR) analyses, and the tissue sections for immunohistochemical analysis. Microarray analysis detected nNOS, eNOS and iNOS at very low expression levels in PBS-treated rats; expression levels were higher for eNOS and iNOS in all VEGF-treated rats. These results were further confirmed by RT-PCR analysis. Immunohistochemical analysis identified the cavernosal endothelium and smooth muscle as the tissue types where eNOS and iNOS were up-regulated, respectively. This is the first report of the induction of both eNOS and iNOS in the penis after intracavernosal VEGF. These events may help support a significant recovery of erectile function after interrupting the blood supply to the penis.

Development of a mathematical model for the prediction of the area of venous leak.

Erectile dysfunction (ED) is an increasingly prevalent medical problem, affecting up to 50% of men aged between 40 and 70-y-old. Many cases are vasculogenic and some of these stem from the inability of the penis to store blood during erection due to leak into the venous system, termed corporo-venocclusive dysfunction (CVOD). The area of leakage during erection could be the most direct measure of erectile function but has not been investigated before. We have developed a simple mathematical model to determine the area of leak during erection and have tested it on data from both normal men (n=3) and men with venogenic impotence (n=16) undergoing dynamic infusion cavernosometry (DIC). The area of leak in the impotent group is significantly greater than in normal men at intracorporal pressures above 30 mmHg and reaches a plateau between 60 and 90 mmHg. Based on this study, we suggest that it may be necessary only to perform DIC at intracorporal pressures between 60 and 90 mmHg.

Is there a role of radial rigidity in the evaluation of erectile dysfunction?

RigiScan has been the most widely utilized device for measuring erectile rigidity. However, the use of the RigiScan in the evaluation of erectile dysfunction has questionable because the RigiScan device does not directly determine axial rigidity. The aim of this study is to clarify that radial rigidity measured by RigiScan reflects the intracorporeal pressure and erectile capability efficiently. From January 1998 to May 1999, a total of 23 patients with erectile dysfunction were involved in the study. They were evaluated by RigiScan and duplex ultrasonography after intracorporeal injection of prostaglandin E1. We investigated the relationship between radial rigidity and the resistance index. The results of radial rigidity were also compared with that of the degree of erection. For the entire group, significant correlations were found between radial rigidity and the resistance index (r=0.680, P<0.001 for tip rigidity; r=0.703, P<0.001 for base rigidity). In addition, for 12 patients whose tip rigidity exceeded 60% and for 10 whose base rigidity exceeded 60%, the correlations between radial rigidity and the resistance index remained (r=0.659, P=0.020 for tip rigidity; r=0.759, P=0.011 for base rigidity). Based on the response determined by patients, radial rigidity represented the degree of erection efficiently. Our findings suggest that RigiScan is a useful diagnostic tool. Radial rigidity represents the intracorporeal pressure efficiently and has an acceptable role in the evaluation of erectile dysfunction.

DIRECT EFFECTS OF SELECTIVE TYPE 5 PHOSPHODIESTERASE INHIBITORS ALONE OR WITH OTHER VASODILATORS ON THE ERECTILE RESPONSE IN CATS

Zaprinast, dipyridamole and sildenafil were injected into the corpora cavernosa of cats to determine whether changes in the steady state level of cyclic guanosine monophosphate (cGMP) induced by inhibiting type 5 phosphodiesterase would cause an erectile response. Increases in intracavernous pressure, penile length and erectile response duration were determined after intracavernous injection of the type 5 cGMP specific phosphodiesterase inhibitors zaprinast, dipyridamole and sildenafil as well as combined zaprinast and prostaglandin E1 (PGE1), and zaprinast and sodium nitroprusside. Systemic arterial pressure was concurrently assessed in these experiments. All responses to phosphodiesterase inhibitors were compared to a control triple drug combination of 1.65 mg papaverine, 0.5 microg PGE1 and 25 microg phentolamine. Each selective type 5 phosphodiesterase inhibitor caused dose related increases in intracorporeal pressure and penile length. However, none of the compounds was as effective as the control drug combination of papaverine, phentolamine and PGE1. Combining zaprinast with sodium nitroprusside led to further increases in pressure and erectile response duration that more closely resembled the control drug response. Combining zaprinast with PGE1 led to a response that was indistinguishable from the control response. The results of these feline studies establish that administering a type 5 phosphodiesterase inhibitor without concomitant administration of a nitric oxide donor or stimulation of the cavernous nerves may have a direct effect on the erectile response. These data also suggest that combining a selective type 5 phosphodiesterase inhibitor with PGE1 may be highly effective local therapy for erectile dysfunction and an acceptable alternative to other current forms of treatment.

INTRAOPERATIVE PHARMACOLOGICAL ERECTION AS AN AID TO PEDIATRIC HYPOSPADIAS REPAIR

The intraoperative evaluation of erection is a major advance in hypospadias surgery. We determined the advantages of erections induced pharmacologically over those induced by intracorporeal saline injection for evaluating chordee during hypospadias surgery. During the repair of hypospadias or chordee without hypospadias 56 boys 6 months to 13 years old underwent pharmacological erection induced by 14 microg. alprostadil administered intracavernously. Phenylephrine (40 microg. ) was given for detumescence. We monitored the adequacy of erection and detumescence, changes in blood pressure and pulse, and in 3 cases intracorporeal pressure. Intraoperative artificial erection was also induced in 30 patients. Erection occurred within 1 minute of injection. It was judged to be excellent in 47 cases and adequate in 6, while it failed in 3 probably due to injection outside of the corpora. Erection involved the whole penis, in contrast to artificial erection when tourniquet placement altered the erection and left the penile base flaccid. The degree of chordee remained stable during evaluation compared to artificial erection when curvature varied with the force of the saline injection. Erection persisted during chordee repair as long as the corpora were not opened. Detumescence occurred within seconds in all cases in which phenylephrine was given. There were no cases of priapism, and systemic blood pressure and pulse did not change. Intracorporeal pressure during pharmacological erection was 47 to 70 mm. Hg, whereas during artificial erection pressure was 50 to 250 mm. Hg depending on how much saline was injected and how rapidly fluid drained through the tourniquet. Chordee was induced by over injection. Pharmacological erection in hypospadias repair is effective and reliable with no significant complications. It is especially valuable in severe hypospadias and in patients with a large suprapubic fat pad. Artificial erection with saline injection should be performed with only moderate force since over filling is unphysiological and may falsely induce chordee.

Evaluation of cadaveric pericardium in the rat for the surgical treatment of Peyronie’s disease

Objectives. To evaluate the intermediate-term efficacy of cadaveric pericardium (Tutoplast) as a grafting material in the surgical correction of Peyronie’s disease using a rat model. Peyronie’s disease is a connective tissue disorder of the tunica albuginea. When less invasive modalities fail to correct the penile deformity, surgical excision of the plaque and coverage with various grafting materials has been advocated. Methods. Twenty male Sprague-Dawley rats (300 to 325 g) constituted the study population. The animals were divided into two groups: group 1, control rats (n = 10) and group 2, rats that underwent wedge excision of the tunica albuginea and replacement with cadaveric pericardial grafts (n = 10). All rats underwent electrical stimulation of the cavernosal nerve to assess erectile function after 4 months. Tissues obtained after death were stained with trichrome and Verhoff’s van Giesen for collagen and elastic fibers. Results. Erectile function as studied by cavernosal nerve stimulation was not significantly different in either group ( P >0.05), and histologic studies of penile cross sections of the pericardial graft group revealed a mild to moderate degree of fibrosis surrounding the patch at 4 months. Conclusions. We found that pericardial cadaveric grafts in a rat model are a suitable tunica albuginea substitute. They allow for penile expansion after cavernosal nerve stimulation and are strong enough to withstand normal intracorporeal pressures. Our early experimental data in the rat support the use of pericardial cadaveric material for coverage of excised Peyronie’s plaques. However, long-term follow-up in humans is mandatory.

Opportunities and challenges in oral therapy.

The major event in normal erectile function is relaxation of the smooth muscle both within the penile arterial system and the cavernosal tissue. The cavernosal smooth muscle is indistinguishable from peripheral vascular smooth muscle from a physiological point of view, ie both are mediated by the NO-cGMP pathway. In man, the major reason for erectile dysfunction (ED) is 'abnormal smooth muscle relaxation', where the smooth muscle of the cavernosa fails to trap blood within the cavernosa (trapping requires a high intracorporeal pressure). The failure of the cavernosal muscle to relax may be due to inadequate stimulation of the muscle or simply non-compliance of the smooth muscle itself. Therefore, attempts to reverse this abnormal smooth muscle relaxation should be directed at either increasing stimulation to the muscle and/or reversing the poor compliance of the muscle tissue itself. Because the major and most efficient pathway for smooth muscle relaxation is the NO-cGMP pathway, any medication that affects this system should prove to be more potent than other alternate pathways of corporal smooth muscle relaxation, as is evidenced from the clinical observations with current intracorporeal instilled drugs. Because the peripheral vascular smooth muscle is indistinguishable physiologically from the muscle of the cavernosal system, any oral drug must be able to differentiate the two smooth muscle compartments to prevent systemic side effects that could render such drugs clinically useless. At the present time, there are no methods to improve smooth muscle compliance but advances in tissue engineering may allow us to accomplish this in the future. International Journal of Impotence Research (2000) 12, Suppl 4, S59-S61.

Magnetic stimulation of the cavernous nerve for the treatment of erectile dysfunction in humans.

A recent study in dogs has demonstrated that magnetic stimulation (MS) of the cavernous nerve produced an increase of the intracorporeal pressure and full penile erection. In view of these results, we tested the possible application of this procedure in humans with erectile dysfunction (ED). The study comprised 32 patients with ED (age 38.3 +/- 9.6 y) and 20 healthy volunteers (age 36.8 +/- 8.8 y). Routine erectile function tests suggested that impotence was neurogenic. A magnetic coil was placed over the dorsal aspect of the penis in the vicinity of the symphysis pubis. MS was performed using a stimulation of 40% intensity, 20 Hz frequency, 50 s on and 50 s off for 10 minutes duration. In the healthy volunteers, the coil was placed as aforementioned but was not activated. The intracorporeal pressure was recorded and penile tumescence and rigidity observed during MS in the patients and without stimulation in the controls. MS led to gradual increase in length and diameter of the penis until full erection was achieved; the penis became firm, rigid and pulsatile. The intracorporeal pressure increased significantly (P < 0.0001) at full erection. Mean latency to full erection was 19.3 +/- 3.4 s. Upon off-stimulation, penile erection and intracorporeal pressure returned to baseline after a mean of 22.7 +/- 3.2 s. Penile and pressure response to MS was resumed after an off-time of 50 s. The response was reproducible infinitely if the off-time was observed. The controls showed no penile tumescence or rigidity or increase of the intracorporeal pressure. In conclusion, MS of the cavernous nerve is effective in inducing penile rigidity. It is a simple, easy and non-invasive method which has no adverse effects. It might prove to be suitable for application in patients with ED.

Experimental hyperprolactinemia in a rat model: alteration in centrally mediated neuroerectile mechanisms.

The purpose of this study was to induce hyperprolactinemia in adult male rats and determine its effect on the central and peripheral mediated neurogenic as well as myogenic mechanisms of erectile function/dysfunction in a rat model. The use of penile reflexes in awake animals was used to test the effect of both central and peripheral mechanisms. Electrical stimulation of the cavernous nervous was used to test peripheral neural function and intracorporal injection of papaverine was used to test the intactness of the corporal smooth muscles. These mechanisms were further explored by administration of testosterone. Eighteen Fisher-344 200-250 g rats aged 10 weeks were used in this study. Group 1 (n = 6) hyperprolactinemia was induced with subcutaneous (SQ) injection of 5 mg rat prolactin (NIDDK-r-PRL-B-7, biopotency 25 IU/mg) in two divided doses daily for 1 week. Testosterone propionate 100 mg/kg dissolved in sesame oil was given intramuscularly on day 1 (weekly dose). Group 2 (n = 6) control animals received SQ injection of vehicle twice daily and sesame oil I/M on day 1. Group 3 (n = 6) received testosterone propionate. Penile reflexes (erections, cups, flips and clusters) were assessed prior to induction (x 3) of and following one-week state of hyperprolactinemia (day 5, 6 and 7). All animals were trained three times before recording the penile reflexes. The penile reflexes being averaged to give a single composite score for each animal. All animals underwent dissections that isolated the cavernosal bodies and cavernosal nerves. Cavernous nerves were activated and intracorporal pressures were recorded at increasing current magnitude (range 0.5-10 mA). Following that corporal smooth muscle reactivity was determined by increasing injection of papaverine (100-3000 microg). Concentration response curves (CRCs) were then generated by plotting percent change (fractional change to make standardized comparison) to increasing neurostimulation or papaverine concentrations at half-log increments. Serum prolactin was determined by rPRL radioimmunoassay Kit-Amersham while serum testosterone was determined Testosterone ELISA Kit-Neogen. Penile reflexes were normal in all groups at the start of experiment but after 1 week of hyperprolactinemia, reflexes were totally abolished in hyperprolactinemia rats (Group 1) and unchanged in Groups 2 and 3. Response to cavernous nerve activation and resulting rise in intracorporal pressure to increasing current (range 0.5-10 mA) were statistically non-significant in any groups. Similarly the intracorporal pressure response to pharmacologic erection induced by papaverine (100-3000 microg) were also non-statistically significant in any groups. Serum prolactin level in all rats receiving prolactin were > 500 ng/ml and the rat group receiving testosterone, serum level were > 20 x higher than the control rat. This approach allowed more clear separation of central and peripheral mechanism of erection. This study shows a central neurological effect of hyperprolactinemia on erectile function. Hypogonadism does not seem to contribute to the impaired penile reflexes as documented by replacement of testosterone did not recover the centrally mediated penile reflexes. Lowered serum testosterone is secondary phenomenon. These observations may have important implications for the understanding, the mechanism and treatment of men with hyperprolactinemia as well as future research in this field.