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Keywords:

  • rat model;
  • partial bladder outlet obstruction;
  • nitric oxide synthase;
  • alfuzosin;
  • erectile function

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

OBJECTIVE

To determine how partial bladder outlet obstruction (PBOO) in a rat model affects erectile function, and whether an uroselective α1-adrenoceptor antagonist, alfuzosin (Sanofi-Aventis, Paris, France) attenuates any erectile dysfunction (ED).

MATERIALS AND METHODS

Adult male Sprague-Dawley rats (120) were randomized into four groups: 1, sham-operated; 2, alfuzosin-treated; 3, PBOO; and 4, alfuzosin-treated with PBOO. Groups 3 and 4 were subjected to PBOO for 6 weeks by ligation of the urethra, while groups 2 and 4 rats received daily oral alfuzosin (10 mg/day) for 6 weeks. In vivo erectile responses were monitored by evaluating ratios of intracavernosal pressure (ICP)/mean arterial pressure, and total ICP (area under the curve). Organ-bath studies were performed on corpus cavernosum smooth muscle (CCSM) strips. Nitric oxide synthase (NOS) expression was determined immunohistochemically (IHC) for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein.

RESULTS

Rats with PBOO showed lower erectile responses than controls. Maximum

electrical field stimulation-mediated and endothelium-dependent acetylcholine-induced relaxations and contractile responses to phenylephrine were significantly reduced in CCSM strips from the PBOO group. The NO donor sodium nitroprusside completely relaxed CCSM from rats in all groups. IHC analyses showed decreased expression of nNOS in PBOO groups compared with controls; by contrast, protein expression of eNOS and iNOS was increased. Alfuzosin-treatment partially attenuated functional and molecular changes in penises of PBOO rats.

CONCLUSION

Rats with PBOO show ED, most likely due to altered NOS expression and NO bioavailability. The α-adrenoreceptor antagonist alfuzosin reversed this ED by altering sympathetic tone, increasing NO-induced relaxation and augmenting blood flow in the penis. This study suggests a rationale for further clinical trials using combinations of α-adrenoceptor antagonists and phosphodiesterase-5 inhibitors in patients with ED and lower urinary tract symptoms.


Abbreviations
ED

erectile dysfunction

(n)(e)(i)NO(S)

(neuronal) (endothelial) (inducible) nitric oxide (synthase)

(CC)SM

(corpus cavernosum) smooth muscle

PBOO

partial bladder outlet obstruction (BOO)

ICP

intracavernosal pressure

MAP

mean arterial pressure

AUC

area under the curve

ACh

acetylcholine

SNP

sodium nitroprusside

EFS

electrical-field stimulation

NANC

nonadrenergic, noncholinergic.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

LUTS are caused by BPH and/or increased sympathetic tone in the bladder neck region [1]. Current epidemiological evidence suggests that there is a meaningful association between BPH/LUTS and sexual dysfunction in ageing men [2]. The Multinational Survey of the Aging Male, using 14 254 men in the USA and Europe, documented an association between LUTS and sexual disorders [3], and implied a common aetiology [4]. Various mechanisms have been proposed to explain the relationship between BPH/LUTS and erectile dysfunction (ED) [2], e.g. decreased nitric oxide synthase/nitric oxide (NOS/NO) levels, increased sympathetic activity with noradrenaline stimulation of α1-adrenoceptors enhanced endothelin and/or Rho-kinase activation affecting intracellular calcium sensitivity, and pelvic atherosclerosis.

The sympathetic nervous system ensures penile flaccidity in the resting state by increasing α-adrenergic tone that augments corpus cavernosum smooth muscle (CCSM) contraction and reduces blood flow into the penis. Blockade of α-adrenoreceptors diminishes α-receptor-mediated contraction of CCSM and facilitates erectile responses [5]. α1-adrenoceptors are recommended as first-line therapy for treating BPH. Alfuzosin, a uroselective α1-adrenoceptor antagonist has benefited men with sexual dysfunction and BPH, with few adverse affects [5,6]. In hypertensive rats, alfuzosin enhanced the number and amplitude of erections induced by apomorphine [7].

A partial BOO (PBOO) experimental animal model was previously developed, using suture ligation [8,9]. This PBOO animal model is generally accepted as representing LUTS resulting from BPH [10]. There are no current studies examining the effect of α-blockers on CCSM function in PBOO rats. Our working hypothesis is that α1-adrenoceptor antagonism might improve ED associated with BPH/LUTS; in the present study we evaluated the effects of an α1-adrenoceptor antagonist on erectile function and further explored the underlying erectile mechanisms in rats with PBOO.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

All experiments were conducted under the standard procedure guidelines of The Tulane University Animal Care and Use Committee. In all, 120 adult male Sprague-Dawley rats (275–300 g; Harlan, Indianapolis, IN, USA) were randomly divided into four groups: group 1 were sham-operated control rats that had a penoscrotal incision with urethral exposure but no urethral ligation; group 2 were control rats treated daily with oral alfuzosin (10 mg/day) for 6 weeks; group 3 were PBOO rats that had a bulbar urethral obstruction created, as described below; and group 4 were PBOO rats treated with alfuzosin. Alfuzosin treatment in group 2 and 4 rats was initiated immediately after surgery to create PBOO. The alfuzosin dose (10 mg/day) selected was based on previous studies [11,12] and represented equivalent in vivo dose recommendations for men with LUTS [5].

The midprostatic urethral obstruction was created via the retropubic approach. After anaesthetic induction with ketamine (80–100 mg/kg i.p.), a 2-cm midline incision was made along the lower abdominal wall, followed by dissection of the underlying muscle and s.c. tissue in groups 3 and 4. The prostatic urethra was carefully isolated such that seminal vesicles, ureters and cavernosal nerves were not violated. Incision and ligature placement was at a distance from the penis, ensuring no direct damage. A sterile 4 F urethral catheter was introduced, and a 3–0 polypropylene nonabsorbable suture was tied around the prostatic urethra containing the catheter. When the suture was secured, the catheter was gently removed, leaving the prostatic urethra partly obstructed. A 4–0 silk suture approximated the overlying muscle layers and the skin was closed.

For the in vivo evaluation of erectile function, 10 rats from each group had the intracavernosal pressure (ICP) monitored. For this, the rats were anaesthetized with sodium pentobarbital (50 mg/kg, i.p), the trachea was exposed and cannulated (PE-240 tubing) to maintain the airway, and the carotid artery was cannulated (PE-50 tubing) to measure the mean arterial pressure (MAP), with a transducer (Statham, Oxnard, CA, USA) attached to a data acquisition system (Biopac MP 100 System, Santa Barbara, CA, USA). A 25 G needle filled with 250 U/mL of heparin and connected to polyethylene tubing was inserted into the right crura of the penis and connected to a pressure transducer to continuously measure ICP. The right major pelvic ganglion and cavernosal nerve were identified. Posterolateral to the prostate on one side, a stainless-steel bipolar-hook stimulating electrode was placed around the cavernosal nerve. The MAP and ICP were measured continuously with pressure transducers. The cavernosal nerve was stimulated (2.5, 5 and 7.5 V, 15 Hz, 30 ms pulse width) with a square pulse stimulator (Grass Instruments, Quincy, MA, USA). The total ICP was determined by the area under the curve (AUC, mmHg/s). Electrical stimulation was initiated distal to the ligature. At the end of the study, the rats were killed, the penises were removed and immediately frozen in liquid nitrogen, and stored at − 80 °C until further processing.

To measure isometric tension, 10 rats from each group were used for organ-bath studies. After anaesthesia, the penis was removed and placed in a Petri dish containing Krebs-bicarbonate solution (containing, mm: NaCl: 118.1, KCl: 4.7, KH2PO4: 1.0, MgSO4: 1.0, NaHCO3: 25.0, CaCl2: 2.5 and glucose: 11.1) and oxygenated with a 95% O2 and 5% CO2. The cavernosal tissue (1 × 1 × 9 mm) was dissected and mounted under 1 g of resting tension in a 20-mL organ bath with one end attached to an electrode holder and the other to a wire connected to a force transducer. Tissue was allowed to equilibrate for 60 min at 37 °C.

In the first series of experiments, dose-response curves for acetylcholine- (ACh, 10−8−10−3m) and sodium nitroprusside- (SNP, 10−8−10−3m) induced relaxations were evaluated after pre-contraction with phenylephrine (10 µm). In addition, cumulative dose-response curves with phenylephrine (10−8−10−3m) were obtained. Also, relaxant effects of alfuzosin (10−8− 10−3m) on phenylephrine-contracted CC strips from all groups was determined.

In the second series of experiments, electrical-field stimulation (EFS) was applied as a train of square-wave pulses (pulse width 0.5 ms, intensity 20 V) at frequencies of 1–20 Hz across paired platinum electrodes placed on either side of the tissue strips. Preparations were pre-incubated for 30 min with guanethidine (5 µm) to eliminate noradrenergic effects, and with atropine (1 µm) to prevent cholinergic responses. After phenylephrine pre-contraction under these conditions, EFS tissue relaxation was mediated by nonadrenergic, noncholinergic (NANC) fibres.

For the immunohistochemical localization of nNOS protein, 6 weeks after PBOO and/or alfuzosin treatment, the cavernosal tissue from penis halves were fixed in 10% formalin and stored until processing for paraffin embedding. Cross-sections (8 µm) were cut and adhered to glass slides. Sections were deparaffinized in xylene and hydrated through graded alcohol baths. Endogenous peroxidases were quenched with 3% H2O2 and nonspecific binding of IgG was blocked using normal horse serum (1:50) in PBS containing 0.1% bovine serum albumin. Slides were treated with 0.1% Triton X-100 for 20 min, washed in PBS for 5 min, and then incubated with rabbit primary polyclonal antibody (anti-nNOS; BD Transduction Laboratories, San Diego, CA, USA) at a dilution of 1:100 for 1 h at room temperature. Samples were then washed and incubated for an additional 30 min with biotinylated secondary antibody (Dako, Carpinteria, CA, USA) followed by a further 30-min incubation with an avidin-biotin-conjugated horseradish peroxidase (Dako) and then the substrate (diaminobenzidine, Vectastain, Vector Laboratories, Peterborough, UK) for 5 min. Harris haematoxylin was used as a counterstain, while negative control slides were stained with only secondary antibody. The images were visualized under light microscopy and a colour digital camera system; nNOS-positive cells appeared as dark brown.

For SDS-PAGE and Western blotting, rat penile tissue was homogenized in lysis buffer (125 mg tissue/mL), the protein extracted and quantified by the bicinchoninic acid method (Pierce Biotechnology, Rockford, IL, USA); 75 µg of protein was loaded per well onto a 7.5% SDS-PAGE gel, then fractionated and transferred to a nitrocellulose membrane by semi-dry electrotransfer for 1 h at 20 V. After soaking in blocking buffer (1 × Tris buffered saline, 0.1% Tween 20, and 5% dry milk), membranes were incubated overnight at 4 °C with primary antibodies (1:1000 for eNOS and iNOS; BD Transduction Laboratories). Blots were developed using horseradish peroxidase-linked secondary antibody (1:5000 goat antirabbit) and a chemiluminescent detection system (LumiGLO, KPL, Gaithersburg, MD, USA). Band intensity was quantified by densitometry (Quantity One, version 4.6.1). The values were normalized to β-actin control and the results expressed as the fold change.

All results are expressed as the mean (sem). For in vivo studies, erectile responses were expressed as the ratio of ICP to MAP measured during the flaccid state and during the plateau phase of the erectile response at each voltage applied. Total ICP was determined by the AUC, from the beginning of cavernosal nerve stimulation until the ICP returned to baseline. For organ-bath studies, isometric force generation was measured as contraction (g tension/g tissue) or as a percentage of the maximum changes in phenylephrine-induced (10 µm) contraction, which was taken as 100%. Statistical differences were determined by anova followed by Bonferroni’s complementary analysis, with P < 0.05 considered to indicate significance.

All drugs were purchased from Sigma Chemical Co. (St. Louis, MO, USA); alfuzosin was obtained from Sanofi-Aventis (Paris, France).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Six weeks after PBOO the total urinary bladder weight increased by four times that in the two control groups (P < 0.001; Fig. 1). This increase in total bladder weight was not evident in PBOO rats treated with alfuzosin for 6 weeks (Fig. 1). There were no differences in the CC strip weights among all groups (data not shown).

image

Figure 1. The mean (sem) bladder weights from the four groups of rats.

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Representative tracings illustrating the effect of PBOO on the erectile response to cavernosal nerve stimulation at 7.5 V for 1 min are shown in Fig. 2. Stimulation of the nerves at 2.5, 5 and 7.5 V produced stimulus-related increases in ICP/MAP and total ICP. At 6 weeks after PBOO the increases in ICP/MAP (Fig. 3a) and total ICP (Fig. 3b) were significantly reduced. After oral treatment with alfuzosin, PBOO had no significant effect on erectile responses to cavernosal nerve stimulation. Treatment of sham-operated control rats with alfuzosin had no significant effect on ICP/MAP (Fig. 3a) or total ICP in response to cavernosal nerve stimulation (Fig. 3b).

image

Figure 2. Representative ICP tracings after cavernosal nerve stimulation at 7.5 V for 1 min in the four groups of rats.

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image

Figure 3. A bar chart showing the voltage-dependent erectile response (a) ICP/MAP and (b) total ICP after cavernosal nerve stimulation for 1 min in the four groups of rats (8–10 rats each); response significantly *P < 0.05, ***P < 0.001 different from group 1.

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Figure 4 indicates that nNOS, as detected by an antibody to the penile variant, was differentially expressed, in multiple cells, presumed to be neurones in these four groups. At 6 weeks after PBOO, there was a significant decrease in abundance of nNOS staining. Treatment with alfuzosin in PBOO rats enhanced the intensity of nNOS staining compared with penile tissues from PBOO rats (Fig. 4).

image

Figure 4. Immunohistochemical localization of nNOS in rat penis (×40). nNOS staining (dark brown) was expressed in the CCSM, presumably depicting nerves. The negative control section processed with no antibodies did not stain (data not shown).

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The relaxation responses to EFS (Fig. 5a) and ACh (Fig. 5b) were significantly lower in CCSM strips from PBOO rats than from sham-operated controls. Treatment with alfuzosin reversed these diminished EFS- and ACh-induced relaxation responses. However, EFS-induced relaxation in group 4 was greater than control values (Fig. 5a). SNP (NO donor) relaxed CCSM in all groups (Fig. 5c). Alfuzosin (10−8−10−5m) by itself gave normal relaxant responses in the CCSM of all groups in a dose-dependent manner (data not shown). While contractile responses to phenylephrine showed a progressive decline, in rats in group 4 the contractile response to phenylephrine was restored (Fig. 6).

image

Figure 5. Graphs showing dose-response curves: (a) EFS (1–20 Hz frequency) induced relaxation (b) acetylcholine (10−8−10−3m) and (c) SNP (10−8− 10−3m) induced relaxation responses in CCSM from all four groups. Data are the mean (sem) of 8–10 rats. *P < 0.05, **P < 0.01 and ***P < 0.001 vs the control group (anova, Bonferroni posthoc).

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image

Figure 6. Graph showing dose-response curves to phenylephrine (Phe; 10−8−10−3m)-induced contraction in groups 2–4. Data are the mean (sem) of 8–10 rats. **P < 0.01 vs control group (anova, Bonferroni posthoc).

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Western blot analysis showed no significant difference in eNOS (Fig. 7) or iNOS (Fig. 8) protein expression in penile tissue from sham-operated controls or alfuzosin-treated rats. eNOS and iNOS protein expressions were increased in penile tissue from PBOO animals compared to controls. While the increased expression of eNOS was completely reversed by alfuzosin treatment for 6 weeks in penile tissue from PBOO rats (Fig. 7), the increase in iNOS protein expression was only partly restored (P < 0.05; Fig. 8).

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Figure 7. (a) Western blot analysis from rat penises show expression of eNOS (140 kDa) protein, 6 weeks after PBOO in groups 1–4 (lanes 1–4, respectively): (b) densitometry analysis of eNOS protein (gel unit/mg protein) from rat cavernosal tissue 6 weeks after PBOO, or alfuzosin treatment (four rats); *P < 0.01, significantly different from sham controls.

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Figure 8. (a) Western blot analysis from rat penises showing expression of iNOS (130 kDa) protein at 6 weeks after PBOO in groups 1–4 (lanes 1–4, respectively): (b) densitometry analysis of eNOS protein (gel unit/mg protein) from rat cavernosal tissue 6 weeks after PBOO, or alfuzosin treatment. (four rats); *P < 0.05 and **P < 0.01 significantly different from sham-controls.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

In this study we evaluated the effect of alfuzosin, a selective α1-adrenoceptor antagonist, on erectile function in a rat model of PBOO. The data show that PBOO in this rat model caused an increase in bladder mass and a decrease in erectile response. Molecular studies showed an increase in iNOS and eNOS expression in the CCSM, while nNOS expression was decreased. Alfuzosin treatment reversed the adverse responses in PBOO rats and restored erectile function. The beneficial effect of alfuzosin on penile erection is probably due to both pro-erectile (relaxant) effects of parasympathetic and NANC pathways leading to activation of the NO/cGMP pathway, and reduction of the anti-erectile effect by the sympathetic effects causing penile detumescence. The use of the control sham group excluded the effect of traumatic injury caused by surgery and ligature placement.

These results support previous studies showing that α-adrenoceptor blockade decreases bladder weight gain in PBOO animals [13]. Similarly, PBOO reduced the in vivo erectile response to cavernosal nerve stimulation and decreased the in vitro relaxant response of CCSM strips to EFS. This might be related to altered bladder variables under conditions of PBOO (e.g. enhanced bladder mass and/or over-distension) and constant compression on the cavernosal nerves (that traverse the bladder neck region) by the urethral ligature. Compression might diminish NANC neuronal innervation of CCSM, and might cause hypoxia and ischaemia, which induce molecular changes. Moon et al.[14] showed that hypoxia and metabolic acidosis (similar to ischaemic priapism) decreased the ICP. A key enzyme responsible for the release of NO from NANC cavernosal nerves is nNOS. In the present study, the molecular mechanism responsible for diminished erectile function appears to involve diminished nNOS levels in the corpora cavernosa, as revealed by immunostaining for nNOS. nNOS levels are known to significantly decrease in a time-dependent manner with experimental ischaemia [15] and in atherosclerosis-induced ED [16]. Antagonism of α1-adrenoceptors might enhance nNOS enzyme activity and thereby augment neuronal NO synthesis and release. Earlier studies showed that α1-adrenoceptors interact with nNOS and modulate adrenergic neurotransmission [17,18]. Similarly in the present study, isolated CCSM from alfuzosin-treated PBOO rats showed a greater relaxation response than sham controls. Hence, improvement in neurogenic relaxation might result from both increased NO release from NANC nerves, and a direct action of alfuzosin. Although alfuzosin can activate soluble guanylate cyclase in NANC neurones, this is unlikely, as the relaxant effect of the CCSM in response to SNP was not altered in alfuzosin-treated PBOO rats. Perhaps the CCSM is less responsive to neuronal NO under hypoxic conditions, which might be enhanced by alfuzosin treatment.

Isolated CCSM strips from PBOO rats showed a reduced response to ACh, suggesting endothelial dysfunction. A recent study by Lin et al.[19] noted impaired relaxation to ACh at 4 weeks of PBOO in a rabbit model, suggesting that hypoxia/ischaemia injury to the endothelium might affect the NO/cGMP pathway. This might explain why eNOS expression by Western blot analysis in the present study was increased in penile tissue from PBOO rats. This paradoxical finding of increased eNOS expression, whereas ACh response is markedly reduced, might be a result of PBOO. Both enhanced eNOS expression and impaired eNOS function have been described in several common clinical conditions, e.g. hypertension [20], diabetes [21] and ageing [22]. According to these reports and the present study, eNOS is probably uncoupled under PBOO conditions due to lack of the substrate l-arginine or the cofactor tetrahydrobiopterine [23]. It was shown that feeding l-arginine reduced the level of bladder impairment and other dysfunctions in PBOO rabbits [24,25]. However, increased expression or activation of uncoupled eNOS isoforms under PBOO conditions alters NO production and causes formation of superoxide anion and peroxynitrite. In addition, other studies revealed that eNOS might also be a source of superoxide anion [23]. NO synthesized by uncoupled eNOS shifts the degradation process and might be responsible for a loss of NO bioavailability and increased endothelial production of anion. BOO increases the generation of reactive oxygen species, resulting in enhanced lipid peroxidation [26]. The present data show up-regulation of iNOS expression in cavernosal tissues of PBOO rats that is reversed by alfuzosin (Fig. 8). However, there are sufficiently high levels of iNOS present in alfuzosin-treated PBOO rats to cause oxidative stress. The beneficial effect of alfuzosin on corpora cavernosal function might be due to normalization of NO bioavailability, re-coupled eNOS and antioxidant effects, as α-receptor antagonists are known to reduce oxidative stress in vascular smooth muscle [27]. Further investigations on the role of oxidative stress and ED linked to LUTS are needed in view of these observations.

The adrenergic nervous system regulates penile detumescence [28]. The present data showed that the contractile response to the α1-adrenoceptor agonist phenylephrine in isolated CCSM strips from PBOO is markedly reduced, and reversed by alfuzosin treatment. It is unclear why contraction to phenylephrine is markedly reduced in CCSM from PBOO rats. Rabbits at 2 weeks of PBOO show greater force generation in response to phenylephrine [29], while at 4 weeks had significantly lower contractile responses [19,29]. In the present study there was a decreased response at 6 weeks of PBOO in rats, while contractility to phenylephrine in human CC is increased in the presence of PBOO [30]. One explanation might be a variation in the contractile response to phenylephrine (e.g. as g contraction vs g/mg or per 100 mg tissue). Also, contractile responses to phenylephrine might depend on the duration and severity of PBOO, species of animal, degree of hypoxia, contraction elicited by noradrenaline, endothelin-1 or potassium, and different interpretation of results [31,32]. The finding that phenylephrine-induced contractions of the CCSM is reduced in PBOO but restored by alfuzosin (an α-adrenoceptor antagonist) appears paradoxical. A potential explanation is that there is a down-regulation of α1-adrenoceptors due to increased sympathetic activity in PBOO. Men with symptomatic BPH are more likely to have increased sympathetic tone [28]. As obstruction can lead to denervation or ischaemia, an α1-adrenoceptor antagonist might decrease sympathetic tone in the penis, thereby permitting full NO-induced relaxation of corporal smooth muscle required for normal erection.

Previous studies have shown that not all α-adrenoceptor antagonists are useful in the treatment of ED [33]. Intracavernosal injection of the α-adrenoceptor antagonist phentolamine alone does not elicit a satisfactory erectile response and the drug is usually used in combination with other vasoactive agents such as papaverine and prostaglandin E1. Based on our data in rats with ED induced by PBOO, in which alfuzosin appears to be useful, it is still unknown whether this agent induces a full erection similar to that from an intracavernosal injection of prostaglandin E1 or papaverine. Thereby, we suggest that the observed tumescence (increase in volume) and rigidity could be evaluated visually in a clinical setting, together with the measurement of arterial systolic pressure and pulse rate before and after alfuzosin injection. In a similar study by Giraldi et al.[34] the α1-adrenoceptor antagonist abanoquil produced both a relaxant effect (contracted tissue strips) and an erectile response (when injected intracavernosally). In these studies there was also priapism leading to long-lasting erections. Other recent studies showed that alfuzosin has a better cardiovascular safety profile, the benefit [35] of once-daily administration, and a better profile for sexual side-effects [36]. Future studies should be designed for both basic and clinical investigations to ascertain if alfuzosin in LUTS/BPH produces abnormal ejaculation. In addition, local vascular changes involving hypoxia due to LUTS-linked ED need to be examined.

Recently we [37] and others [38] hypothesized that urogenital cells up-regulate the secretion of several growth factors, suggesting that hypoxia can trigger prostatic growth. Future research is required to determine the exact relationship between LUTS and male sexual dysfunction. This might represent an action independent of the beneficial effect on LUTS, as the positive effect of alfuzosin on sexual function was reported in patients with LUTS/BPH.

In conclusion, the mechanisms underlying PBOO-induced ED are multifactorial, including decreased pro-erectile and enhanced anti-erectile effects caused by alterations of NOS isoform expression. In PBOO there is constant compression of the NANC, adrenergic and parasympathetic nerves and vessels at the base of the bladder by urethral ligation. This might cause denervation and ischaemia of cavernosal nerves and endothelial cells, thereby impairing corporal smooth muscle relaxation and altering erectile function. Reactive oxygen species-induced tissue damage might also be implicated during more prolonged periods of BOO. The relaxant effect of alfuzosin in the penis appears to involve both the parasympathetic and NANC pathways, leading to activation of the NO/cGMP pathway, and sympathetic activity that controls penile detumescence. Alfuzosin reduces oxidative stress-induced changes associated with prolonged PBOO.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This work was supported by an investigator-initiated independent research grant from Sanofi-Aventis (Paris, France).

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Wayne J. G. Hellstrom is an investigator and speaker for Sanofi-Aventis.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES