R.J. Morgan

Does severity of ischaemic coronary disease correlate with erectile function

An association between diminution in the quality of male sexual function and ischemic coronary disease has been suggested. Patients with ischemic heart disease who underwent coronary angiography participated in this study which aimed to document the impact of the extent of coronary disease upon sexual function in 40 patients (mean age 56.6 y). The 11-questions accepted questionnaire addressing sexual drive, erectile function, and ejaculation was used. Information regarding, age, medications, hypertension, diabetes, relevant risk factors, medical history, and the number of occluded coronary vessels was retrieved from the patients’ records. A statistically significant correlation was demonstrated between erectile function and the number of coronary vessels involved. Patients with one-vessel disease had more (P<0.04) and firmer erections (P<0.001) with fewer difficulties in achieving an erection (P<0.007) than men with two- or three-vessel disease. Age, diabetes, and hypertension also had a negative effect on the quality of the erection (P<0.05) in all patients.

Platelets, oxidant stress and erectile dysfunction: an hypothesis

Time for primary review 30 days. The successful use of sildenafil (Viagra™) to treat vasculogenic erectile dysfunction (VED) has heightened awareness of the widespread prevalence of this disorder [1–3]. Sildenafil acts through the augmentation of nitric oxide (NO) actions on vascular/corpus cavernosal smooth muscle cell relaxation [1–4] (Fig. 1). Thus, the therapeutic use of sildenafil has also highlighted the central role played by NO in mediating normal erection and in the pathogenesis of VED. Nevertheless, we still know little about the basic pathophysiology of VED. Since prevention is preferable to cure, it is imperative to improve our understanding of the pathophysiology of VED. In this brief review, we suggest that another major consequence of diminished NO formation is the increased adhesion of platelets and leukocytes, in particular neutrophils, which may counter erection through release of vasconstrictors, superoxide and other oxygen free radicals. We also suggest that erection itself may trigger events that contribute to exacerbation of the disorder in the long-term, again through the adhesion of platelets and leukocytes. Fig. 1 Key events in normal penile erection — the central role of NO. Upon sexual arousal, sympathetic drive initiates erection through both sympathetic and non-adrenergic, non-cholinergic (NANC) innervation of the corpus cavernosum and pudendal arteries. NANC fibres release NO and acetylcholine stimulates the release of NO from local endothelium by activation of NO synthase (NOS). NO promotes relaxation of arterial and cavernosal smooth muscle through activation of guanylate cyclase and suppression of activator Ca2+ which in turn results in erection. It is now well established that impairment of the above systems is central to the aetiology of vasculopathic erectile dysfunction. Sildenafil promotes erection through inhibition of type V phosphodiesterase which blocks the metabolism of cGMP to inactive GMP. Thus, cGMP accumulates thereby promoting relaxation of the relevant VSMCs. Patients with … * Corresponding author. Tel.: +44-117-928-3154; fax: +44-117-929-9737 j.y.jeremy{at}bristol.ac.uk

Up-regulation of endothelin (ETA and ETB) receptors and down-regulation of nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet obstruction

Abstract Bladder outlet obstruction (BOO) is associated with altered bladder structure and function. Endothelin-1 (ET-1) has mitogenic and potent contractile properties. There are two ET receptors: ETA and ETB. Nitric oxide synthase (NOS) is the enzyme responsible for the synthesis of nitric oxide (NO) which is involved in smooth muscle relaxation. We investigated whether there are any changes in the density of ET-receptors and NOS in the detrusor and bladder neck in a rabbit model of BOO. Partial BOO was induced in adult male New Zealand White rabbits. Sham operated age-matched rabbits acted as controls. After six weeks the urinary bladders were excised and detrusor and bladder neck sections incubated with radioligands for ET-1, ETA and ETB receptors and with [3H]–l-NOARG (a ligand for NOS). NADPH histochemistry was also performed. BOO bladder weights were significantly increased (P=0.002). ET-1 binding and ETA receptor binding sites were significantly increased in the BOO detrusor smooth muscle (P=0.04, P=0.03 respectively) and urothelium (P=0.002, P=0.02 respectively). ETB receptor binding sites were also significantly increased in the BOO detrusor smooth muscle (P=0.04). However, there was no change in the BOO bladder neck. NOS was significantly decreased in the detrusor smooth muscle (P=0.003) and urothelium (P=0.0002). In the bladder neck NOS was also significantly reduced in the urothelium (P=0.003). NADPH staining was decreased in the detrusor and bladder neck. The up-regulation of ET receptors along with the down-regulation of NOS in the detrusor may contribute to the symptoms associated with BOO. Since ET-1 has a mitogenic role, especially via its ETA receptors, the increase in ETA receptors may also be involved in detrusor hyperplasia and hypertrophy in BOO. ET antagonists may therefore have a role in the treatment of patients with BOO.

Down-regulation of endothelin-B receptor sites in cavernosal tissue of a rabbit model of partial bladder outlet obstruction: potential clinical relevance.

Abstract Erectile dysfunction (ED) is a common problem that significantly affects quality of life and psychological well-being. Benign prostatic hyperplasia (BPH) is the commonest known benign proliferative disorder. Recently there has been growing evidence to suggest that patients with high BPH symptom scores have an increased incidence of ED. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is thought to play an important role as a modulator of erectile physiology and dysfunction. We investigated whether there were any changes in the penile histology and in the density and distribution of ET-1 and its receptor subtypes in the corpora cavernosa of a rabbit model of partial bladder outflow obstruction (BOO). BOO was induced in 12 adult New Zealand White rabbits; 12 sham-operated rabbits acted as controls. Penises were excised after 3 and 6 weeks (n=6 each for control and BOO). Low- and high-resolution autoradiography was performed using radioligands for ET-1, ETA and ETB receptors and the results were analysed densitometrically. Ultrastructural evaluation of the corpus cavernosum (CC) was also performed. ET-1, ETA and ETB receptor-binding sites were primarily localised to the smooth-muscle cells (SMC) of the CC and to the endothelium lining the cavernosal space. ETB receptor-binding sites were significantly decreased (P=0.04) in the 6-week BOO cavernosal tissue. These receptor changes were accompanied by ultrastructural changes in the CC. ET-1 may play a role in the pathophysiology of ED associated with BPH. This may partly be due to enhanced vasoconstrictor actions and SMC proliferation secondary to a reduction in ETB receptors. Further work is needed to evaluate this possibility.

Time-dependent up-regulation of neuronal 5-hydroxytryptamine binding sites in the detrusor of a rabbit model of partial bladder outlet obstruction

Abstract Serotonin (5-hydroxytryptamine; 5-HT), a vasoactive bioamine with potent contractile activity, is thought to act indirectly in the urinary bladder by the stimulation of its presynaptic receptors. This results in the release of acetylcholine (ACh), which then acts on muscarinic receptors to produce bladder contractility. Bladder outlet obstruction (BOO) can lead to detrusor instability associated with denervation supersensitivity to ACh. Using a rabbit model of partial BOO, we investigated whether there were any associated changes in the neuronal 5-HT binding sites. Partial BOO was induced in adult male New Zealand White rabbits. Sham-operated age-matched rabbits acted as controls. After 1, 3 and 6 weeks the urinary bladders were excised. Detrusor sections were incubated with [3H]-5-HT. Autoradiographs were generated and analysed densitometrically. The presence of nerves was detected using immunohistochemistry with NF200. Autoradiography demonstrated a time-dependent, significant (P < 0.0001) up-regulation of [3H]-5-HT binding sites in the detrusor smooth muscle after the induction of BOO. Immunohistochemistry confirmed that the [3H]-5-HT binding sites were neuronal. In the rabbit model of partial BOO there was a significant time-dependent up-regulation of neuronal [3H]-5-HT binding sites in the detrusor. This change may influence 5-HT-mediated ACh release, resulting in increased bladder contractility. This, in turn, may play a role in detrusor instability associated with denervation post-junctional supersensitivity. These results provide a possible rationale for further investigation into the use of 5-HT antagonists in the treatment of detrusor instability associated with BOO.

Enhanced relaxation of diabetic rabbit cavernosal smooth muscle in response to nitric oxide: potential relevance to erectile dysfunction

New Zealand white rabbit cavernosal smooth muscle strips (n=6) were mounted in organ baths. Relaxations to nitric oxide (10−7–10−4 mol/l) were measured and the same procedure was repeated on strips from rabbits 6 months after alloxan-induced diabetes (n=6). Transverse cavernosal sections were obtained from the same penises. Low and high resolution autoradiographs were prepared using [3H]-L-NG-nitroarginine (an index of nitric oxide binding sites) and analysed densitometrically. Histochemical analysis was performed on adjacent sections using NADPH diaphorase (an index of nitric oxide synthase activity).Nitric oxide relaxed control rabbit cavernosal smooth muscle strips in a concentration-dependent manner. Diabetic rabbit cavernosal smooth muscle strips were significantly (P<0.03) more sensitive to nitric oxide (mean IC50=3.9 × 10−6 mol/l). Nitric oxide synthase binding sites were localised to the cavernosal endothelium and smooth muscle. Nitric oxide synthase activity was increased in 6 month diabetic cavernosal smooth muscle. These findings suggest impairments in the L-arginine-nitric oxide pathway may play a role in the pathophysiology of diabetic erectile dysfunction.

Sexual dysfunction in men with lower urinary tract symptoms and benign prostatic hyperplasia: an emerging link

The authors also state ‘conflicting evidence has been generated’ and also ‘evidence-based knowledge to date implied...’. It is because of the lack of a properly conducted double-blind, clinically controlled trial showing clear evidence of any danger of these medications that I have continued to carry on with their use, because the risk of cardiovascular or cerebrovascular incidence is greater than the risk of bleeding and the need for transfusion.

Inhibition of diabetic bladder smooth muscle cell proliferation by endothelin receptor antagonists.

Abstract Urinary bladder hypertrophy and hyperplasia are well recognised in diabetic cystopathy. The urinary bladder is known to synthesise endothelin-1 (ET-1), a potent vasoconstrictor peptide with mitogenic properties. Using diabetic New Zealand White (NZW) rabbits, we investigated the potential role of ET receptor subtypes (ETA and ETB) on the proliferation of bladder smooth muscle cells (SMC). Diabetes mellitus was induced in adult male NZW rabbits. After 6 months, control (n=6) and diabetic (n=6) bladders were removed and SMC from the dome and bladder neck were grown using standard explant methodology. At passage two, the cells were made quiescent and then further incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or diabetic rabbit serum (DRS) in the presence or absence of ETA-antagonist (BQ123) or ETB-antagonist (BQ788). SMC proliferation was then measured with 5-bromo-2′deoxy-uracil 24 h later and by cell counting (using a haemocytometer) at 48 h. Neither BQ123 nor BQ788 influenced detrusor or bladder neck SMC proliferation in FCS or CRS. However, in the presence of DRS, BQ123 and BQ788 significantly inhibited diabetic detrusor and bladder neck SMC proliferation at 30 and 100 nmol/l (P < 0.03 and P < 0.01, respectively). Cell counts were also significantly reduced from the diabetic detrusor and bladder neck (P < 0.01 and P < 0.03 with BQ123 and BQ788, respectively). These results suggest that ET may play a pathophysiological role in the bladder SMC hyperplasia associated with diabetes mellitus.

5-Hydroxytryptamine-induced potentiation of cholinergic responses to electrical field stimulation in pig detrusor muscle.

Sir, We read with interest the paper by Sellers et al. [1], who elegantly reported 5-hydroxytryptamine (5-HT) potentiation of cholinergic responses to electrical ®eld stimulation in pig bladder strips. These authors speculated that altered 5-HT modulation of cholinergic responses might play a role in bladder dysfunction. The authors based their hypothesis on previous studies, which have postulated that altered cholinergic responses may be a possible cause of detrusor instability associated with BOO. We also considered the possible role of 5-HT in bladder dysfunction associated with BOO. To this effect we showed, in a rabbit model of partial BOO, that there is a signi®cant time-dependent upregulation of neuronal 5-HT binding sites in the detrusor [2]. We also showed that doxazosin, an a-antagonist used in treating BPH, signi®cantly inhibits 5-HT-mediated contractions in the rabbit detrusor [3]. Autoradiography showed that doxazosin reduced 5-HT binding to receptor sites in a concentration-dependent manner in this tissue [3]. Hence, we speculated that the bene®cial effects of doxazosin in BOO may be ascribable, at least in part, to 5-HT antagonism. These ®ndings support the hypothesis that 5-HT contributes to the pathogenesis of bladder dysfunction.

Intracavernosal PGE1-related penile fibrosis: possible mechanisms.

The editorial comment made by Professor Porst on penile ®brosis following intracavernosal (i.c.) prostaglandin E1 (PGE1) injection therapy for erectile dysfunction is very timely. We reported a 10% incidence of distal penile ®brosis following long-term use of i.c. PGE1. In this study, this complication was not related to the injection site as the lesions occurred distally. Since these patients achieved a grade IV erection lasting between 1±2 h, the development of ®brosis could not have been associated with inadequate erections. To explain why our patients developed distal penile ®brosis, we suggest two mechanisms. Firstly, it is well known that with aging there is signi®cant reduction of elastic ®bers in both layers of the tunica albuginea. As a result, there is a signi®cant decrease in the elasticity of both the inner and septal ®brous layers supporting the tunica albuginea. Reduction in elastic ®bres and its elasticity prevents the corpora from tolerating relatively high i.c. pressures during PGE1-induced erections. This may result in tunical tears, disruption of small blood vessels, bleeding and clot formation. This could subsequently result in ®brosis. Secondly, an ischaemic injury to the tunica albuginea may be involved in distal penile ®brosis. Assessment of blood ̄ow by duplex sonography has shown a signi®cant reduction in the blood ̄ow velocity in a proximo-distal direction following i.c. vasoactive injections. Furthermore, the cavernous oxygen tension is signi®cantly lower after i.c. injection of PGE1 in arteriogenic and venogenic groups, compared to controls. In animal experiments, there is shunting of blood from the subtunical space into the deep cavernosal circulation during both pelvic nerve and pharmacological stimulation. This shunting is more marked after pharmacological stimulation causing a greater drop in the subtunical oxygen tension in this group. These changes may be responsible for inducing relative ischaemia and may have contributed to the formation of distal ®brosis in our patients. A more careful titration of the dose of PGE1 may reduce the incidence of distal penile ®brosis. The minimally effective dose, which achieves an adequate erection for the minimum length of time needed for patient satisfaction, should be used.