Ferdinando Fusco

Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation

Hydrogen sulfide (H2S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). l-Cysteine (l-Cys) acts as a natural substrate for the synthesis of H2S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert l-Cys to H2S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H2S [sodium hydrogen sulfide (NaHS)] or l-Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum. l-Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and l-Cys promote penile erection, and the response to l-Cys is blocked by PAG. Our data demonstrate that the l-Cys/H2S pathway mediates human corpus cavernosum smooth-muscle relaxation.

A First Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating Extracorporeal Shock Wave Therapy for the Treatment of Peyronie's Disease

BACKGROUND Extracorporeal shock wave therapy (ESWT) is a conservative therapy for patients with Peyronies disease (PD). OBJECTIVE To investigate the effects of ESWT in patients with PD. DESIGN, SETTING, AND PARTICIPANTS One hundred patients with a history of PD not >12 mo who had not had previous PD-related treatments were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Patients were randomly allocated to either ESWT (n=50) or placebo (n=50). Erectile function (EF), pain during erection, plaque size, penile curvature, and quality of life (QoL) were assessed at baseline, at 12 wk, and at 24 wk follow-up. INTERVENTION Four weekly treatment sessions were administered. Each ESWT session consisted of 2000 focused shock waves. For the placebo group, a nonfunctioning transducer was employed. MEASUREMENTS EF was evaluated with the shortened version of the International Index of Erectile Function (IIEF-5), pain was evaluated with a visual analog scale (VAS; 0-10), plaque size was measured in cm(2), and penile curvature was measured in degrees. RESULTS AND LIMITATIONS After 12 wk, mean VAS score, mean IIEF-5 score, and mean QoL score ameliorated significantly in patients receiving ESWT. Mean plaque size and mean curvature degree were unchanged in the ESWT group, while a slight increase was reported in the placebo group (p-value not significant vs baseline). After 24 wk, mean IIEF-5 score and mean QoL score were stable in the ESWT group, while mean VAS score was significantly lower when compared with baseline in both groups. Interestingly, after 24 wk, mean plaque size and mean curvature degree were significantly higher in the placebo group when compared with both baseline and ESWT values. The main limitations were that the QoL questionnaire was not validated, ED was not etiologically characterized, and inclusion criteria were restricted. CONCLUSIONS In patients with PD, ESWT leads to pain resolution and ameliorates both EF and QoL.

Involvement of β3-adrenergic receptor activation via cyclic GMP- but not NO-dependent mechanisms in human corpus cavernosum function

The β3-adrenoreceptor plays a major role in lipolysis but the role and distribution of β3-receptors in other specific sites have not been extensively studied. β3-adrenergic receptors are present not only in adipose tissue but also in human gall bladder, colon, prostate, and skeletal muscle. Recently, β3-adrenergic receptor stimulation was shown to elicit vasorelaxation of rat aorta through the NO–cGMP signal transduction pathway. Here we show that β3-receptors are present in human corpus cavernosum and are localized mainly in smooth muscle cells. After activation by a selective β3-adrenergic receptor agonist, BRL 37344, there was a cGMP-dependent but NO-independent vasorelaxation that was selectively blocked by a specific β3-receptor antagonist. In addition, we report that the human corpus cavernosum exhibits basal β3-receptor-mediated vasorelaxant tone and that β3-receptor activity is linked to inhibition of the RhoA/Rho-kinase pathway. These observations indicate that β3-receptors may play a physiological role in mediating penile erection and, therefore, could represent a therapeutic target for treatment of erectile dysfunction.

Sildenafil effect on the human bladder involves the L-cysteine/hydrogen sulfide pathway: a novel mechanism of action of phosphodiesterase type 5 inhibitors.

BACKGROUND Phosphodiesterase type 5 inhibitors (PDE5-Is) are effective in the treatment of lower urinary tract symptom (LUTS), although their mechanism of action is still unclear. PDE5-Is cause bladder detrusor relaxation, and this effect is partially independent of nitric oxide. Hydrogen sulfide (H(2)S) is a newly discovered transmitter with myorelaxant properties. It is predominantly formed from L-cysteine by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). OBJECTIVE To evaluate whether the L-cysteine/H(2)S pathway contributes to the relaxing effect of sildenafil on the human detrusor dome. DESIGN, SETTING, AND PARTICIPANTS Samples of bladders obtained from men undergoing open prostatectomy for benign prostatic hyperplasia (BPH) were used. The presence of CBS and CSE enzymes was assessed by western blot. H(2)S production was measured by a colorimetric assay in basal and stimulated conditions with L-cysteine and in response to sildenafil (1, 3, 10, and 30 μM), 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP; 100 μM) or dibutyryl-cyclic adenosine monophosphate (dibutyryl-cAMP; 100 μM). A curve concentration effect of sodium hydrosulfide (NaHS), H(2)S donor (0.1 μM to 10mM), L-cysteine (0.1 μM to 10mM), and sildenafil (0.1-10 μM) was performed on precontracted detrusor dome strips. To investigate H(2)S signaling in a sildenafil effect, CBS and CSE inhibitors were used. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Analysis of variance was used, followed by the Bonferroni post hoc test. RESULTS AND LIMITATIONS CBS and CSE are present in the human bladder dome and efficiently convert L-cysteine into H(2)S. Both NaHS and L-cysteine relaxed human strips. Sildenafil caused (1) a relaxation of bladder dome strips and (2) a concentration-dependent increase in H(2)S production. Both effects were significantly reduced by CBS and CSE inhibitors. Similar to sildenafil, both 8-bromo-cGMP and dibutyryl-cAMP caused an increase in H(2)S production. CONCLUSIONS The sildenafil relaxant effect on the human bladder involves the H(2)S signaling pathway. This effect may account in part for the efficacy of PDE5-Is in LUTS. A better definition of the pathophysiologic role of the H(2)S pathway in the human bladder may open new therapeutic approaches.

Neurophysiologic evaluation of central-peripheral sensory and motor pudendal pathways in primary premature ejaculation

OBJECTIVES Pudendal nerve somatosensory evoked potentials (SEPs), the bulbocavernosus (BC) reflex, and BC perineal motor evoked potentials after transcranial magnetic cortical stimulation were performed in patients with primary premature ejaculation to investigate the somatic sensory and motor function of the genital area. METHODS Fourteen patients with primary premature ejaculation underwent psychological counseling, urologic physical examination, transrectal ultrasound examination, laboratory testing, and the Stamey test. The spinal and cortical pudendal nerve SEPs were performed by dorsal nerve stimulation at the penile shaft (DN-SEPs) in all patients and at the glans penis (GP-SEPs) in 3 of them. The BC reflex was obtained by stimulating the base of the penis. RESULTS The mean sensory threshold did not significantly differ between the patients and normal subjects. Cortical DN-SEPs were normal in all patients. The sensory central conduction time, calculated in 6 patients, was normal. The mean cortical DN-SEP amplitude was significantly smaller in patients than in controls. In 3 patients and in 3 controls who underwent both DN-SEP and GP-SEP testing, the glans penis sensory threshold was lower than the dorsal nerve threshold and the cortical GP-SEP latency was longer than the cortical DN-SEP latency. The BC reflex was normal in most patients. The BC motor evoked potentials were normal in all patients, but one. CONCLUSIONS We did not confirm either a faster conduction along the pudendal sensory pathway or a greater cortical representation of the sensory stimuli from the genital area in our patients. Moreover, we did not confirm hyperexcitability of the BC reflex in them. Our results suggest that the electrophysiologic approach is probably not sufficient to clarify the causes of primary premature ejaculation. A more integrated investigation could allow better results in this field.

Tadalafil and vardenafil vs sildenafil: a review of patient-preference studies.

The immediate objective of phosphodiesterase type 5 (PDE5) inhibitor treatment is to restore the ability of a man to achieve and/or maintain an erection adequate for sexual intercourse. As erectile dysfunction (ED) generally develops in the second half of life, the ultimate objective generally is not procreation, but quality of sexual life. Indeed, ED is known to impair quality of life considerably; two‐thirds of men report that ED has impaired their self‐esteem and nearly a third claim that it has damaged the relationship with their partner. It follows that the therapeutic success of PDE5 inhibition has an important subjective component, which is compounded by the subjective nature and complexity of sexual life in humans. This makes it very difficult for physicians to be certain that they have selected the optimal therapy for a couple, even after a thorough evaluation. The 2007 European Association of Urology Guidelines stress the importance of educating the patient and claim that ‘the patient will choose the final drug after his own experience’. However, PDE5 inhibitors are typically used twice a week, so a patient would have to spend ≈3 months trying the various compounds and dosages to achieve adequate exposure to all three PDE5 inhibitors; this would seem an unrealistic strategy in normal clinical practice. The acknowledgement that the patient has an important role in therapeutic decisions for ED has fuelled interest in the concept of patient preference. It has been established that patient preference depends on three factors, i.e. personal characteristics, e.g. age, duration of ED, frequency and dynamics of sexual relations, and the characteristics of their partners, e.g. age, menopausal status and level of interest in sexual activity and medication profile. Medication features of interest include efficacy in terms of quality of erection, consistency of effects, rapid onset of action, long duration of action, side‐effect profile and route of administration; drug costs must also be considered if the medicinal product is not reimbursed.

Tadalafil once daily and extracorporeal shock wave therapy in the management of patients with Peyronie’s disease and erectile dysfunction: results from a prospective randomized trial

Extracorporeal shock wave therapy improves erectile function in patients with Peyronies disease. However, erectile dysfunction still persists in many cases. We aimed to investigate the effects of extracorporeal shock wave therapy plus tadalafil 5 mg once daily in the management of patients with Peyronies disease and erectile dysfunction not previously treated. One hundred patients were enrolled in a prospective, randomized, controlled study. Patients were randomly allocated to receive either extracorporeal shock wave therapy alone for 4 weeks (n = 50) or extracorporeal shock wave therapy plus tadalafil 5 mg once daily for 4 weeks (n = 50). Main outcome measures were: erectile function (evaluated through the shortened version of the International Index of Erectile Function), pain during erection (evaluated through a Visual Analog Scale), plaque size, penile curvature and quality of life (evaluated through an internal questionnaire). Follow-up evaluations were performed after 12 and 24 weeks. In both groups, at 12 weeks follow-up, mean Visual Analog Scale score, mean International Index of Erectile Function score and mean quality of life score ameliorated significantly while mean plaque size and mean curvature degree were unchanged. Intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and quality of life score in patients receiving the combination. After 24 weeks, intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and mean quality of life score in patients that received extracorporeal shock wave therapy plus tadalafil. In conclusion extracorporeal shock wave therapy plus tadalafil 5 mg once daily may represent a valid conservative strategy for the management of patients with Peyronies disease and erectile dysfunction.

Our Experience on the Association of a New Physical and Medical Therapy in Patients Suffering from Induratio penis plastica

Objectives: To check the efficiency of shock waves in the treatment of induratio penis plastica. The Minilith SL1, successfully used in orthopedic or salivary stones because of its lithotriptic power, can be used to break plaques in Peyronie’s disease. Methods: A total of 130 patients affected with Peyronie’s disease were entered into a prospective trial. Patients with completely calcified plaques as determined by ultrasound evaluation were excluded. We divided the patients into three treatment groups: (A) shock waves alone in 21 patients; (B) a combination of shock waves and verapamil (perilesional injection) in 36 patients, and (C) verapamil alone in 73 patients. First, we treated all groups A and B patients 3 times, 20 min each time, with a Minilith SL1, and then only the patients of the second group received a complete cycle of twelve injections of verapamil (10 mg) every 2 weeks for 6 months. The group of 73 patients (group C) treated during the previous 2 years with a medical therapy (only injection of verapamil) was used as a control group. Results: Ultrasound evaluation showed a reduction of plaque in 11/21 group A patients and 7/36 group B patients. The treatment was tolerated very well and only 11 petechiae in some patients were noticed after ESW treatment. Conclusions: The therapeutic association of shock waves with verapamil injection is an effective nonoperative treatment for the stabilization of Peyronie’s disease.

A New Biopsy Technique to Investigate Peyronie’s Disease Associated Histologic Alterations: Results with Two Different Forms of Therapy

OBJECTIVES Peyronies disease is the most frequent cause of penile curvature and occurs particularly in middle-age patients. The best technique for penile biopsy, in the evaluation of albuginea and cavernous tissue, has not been delineated yet. We present a new technique of penile biopsy, useful in the study of Peyronies plaque, fibrosis and erectile dysfunction or any other pathological condition of the penis requiring a biopsy. METHODS A treatment group (A) of 380 patients underwent Extra Shock Waves Treatment (ESWT) three times a week for 20 minutes, followed by a complete cycle of 12 injections of verapamil (10mg), every two weeks for six months. A control group (B) of 92 patients underwent verapamil injections alone. Three months after the end of the treatment, each patient underwent penile biopsy performed with Acu-Punch (Acuderm Inc.), a biopsy-punch armed with a well-sharpened rotating cylindrical blade, first used by dermatologists for cutaneous lesions. RESULTS A reduction of the plaque volume was found in 260/380 patients (68.4%) of group A and in 28/92 (30.4%) of group B; painful erection weaned off in 312/340 patients of group A (91.7%) and in 36/82 patients (43.9%) of group B. In all 472 patients an excellent specimen was obtained and both the tunica albuginea and the cavernous tissue were easily identified. In the 260 cases, in which the Extra Shock Waves Treatment was successful, scanning and transmission electron microscopy demonstrated a reduction in packing and clumping of the collagen fibers. CONCLUSIONS This new technique of penile biopsy with Acu-Punch can replace surgical biopsies when a surgical operation is not indicated. Such a low-invasive technique could be performed in all cases of Peyronies disease and allows a more extensive use of microscopic analysis in the study of Peyronies disease.

Androgens and morphologic remodeling at penile and cardiovascular levels: a common piece in complicated puzzles?

CONTEXT Epidemiologic data demonstrate a protective role by normal androgen levels on cardiovascular health and erectile function. Low androgen levels are associated with erectile dysfunction and increased risk of cardiovascular diseases. Both conditions recognize as anatomic substrate a pathologic structural remodeling. Direct androgen effects on male external genitalia, vascular wall, and myocardium have been reported. OBJECTIVE To review current knowledge about androgen-dependent molecular signaling pathways and cellular events within penile and cardiovascular tissues involved in the homeostatic control of morphologic tissue properties and in the development of structural remodeling in presence of normal and low androgen levels, respectively. EVIDENCE ACQUISITION A literature search was performed in November 2008 using the commercially available Medline online engine search to retrieve studies (from 1998 to 2008) on the mechanisms mediating the role of androgens on penile and cardiovascular morphologic homeostasis and remodeling. A combination of the following medical subject headings was used: androgens, hypogonadism, vessel tissue architecture, remodeling, cardiovascular system, and penis. EVIDENCE SYNTHESIS Androgens exert direct beneficial effects on both cardiovascular and penile tissues. Endothelial cells and smooth-muscle cells are the main cellular targets for direct androgen effects in both tissues and are involved in pathologic remodeling in hypogonadal models. At vascular level, androgens promote endothelial cell survival, reduce endothelial expression of proinflammatory markers, and inhibit proliferation and intimal migration of vascular smooth-muscle cells. At penile level, low androgen levels are associated with apoptosis of endothelial cells and smooth-muscle cells. Moreover, low androgen levels impair proliferation, migration, and homing of endothelial progenitor cells as well as myogenic differentiation of mesenchymal progenitor cells. CONCLUSIONS Normal androgen levels promote vascular and penile homeostasis by direct mechanisms mainly involving endothelial cells and smooth-muscle cells. Low androgen levels are associated with impairments of such mechanisms, leading to pathologic structural remodeling.