Nitric oxide/cyclic guanosine monophosphate signalling mediates an inhibitory action on sensory pathways of the micturition reflex in the rat.

BACKGROUND: Overactive bladder can be associated with a hyperexcitability of bladder afferent C-fibres. Several studies have suggested that nitric oxide (NO) or its downstream signalling could modulate the micturition reflex (MR) by reducing the excitability of bladder afferents. OBJECTIVES: To evaluate the role of the NO/cyclic guanosine monophosphate (cGMP) signalling pathway on the MR in a model of bladder hyperactivity (BHA) associated with C-fibre activation in the rat. DESIGN, SETTING, AND PARTICIPANTS: Adult female Sprague Dawley rats were used. MEASUREMENTS: Cystometry was performed in anaesthetised rats. The effects of 0.1 mg/kg of sodium nitroprusside (SNP), an NO donor; 10 mg/kg of 8Br-cGMP, a cGMP analogue; 3 mg/kg of sildenafil and 1 mg/kg of vardenafil, two phosphodiesterase type 5 inhibitors (PDE5-I); 10 mg/ml of L-N(G)-nitroarginine methyl ester (L-NAME), an NO synthase inhibitor; and 1 mg/kg of LY-83583, a guanylate cyclase inhibitor, were investigated on BHA during intravesical capsaicin (30 micromol/l) instillation. All drugs were delivered intravenously except for L-NAME, which was intravesically administered. RESULTS AND LIMITATIONS: SNP, 8Br-cGMP, and PDE5-I increased the intercontraction interval (ICI), while SNP and PDE5-I increased the micturition pressure threshold (MPT). L-NAME and LY-83583 decreased MPT, and L-NAME decreased ICI. 8Br-cGMP decreased the maximum intravesical pressure (MP), contrary to L-NAME and LY-83583. SNP and PDE5-I had no effect on MP. SNP increased the voided volume (VV). PDE5-I and 8Br-cGMP also increased VV, although not significantly. In contrast, L-NAME tended to decrease VV. Although 8Br-cGMP decreased the baseline intravesical pressure, LY-83583 increased it. Neither SNP nor PDE5-I nor L-NAME had any effect on baseline pressure. CONCLUSIONS: Compounds activating the NO/cGMP pathway inhibited BHA, whereas compounds inhibiting the NO/cGMP pathway increased it. These results indicate that the NO/cGMP signalling pathway is involved in the regulation of the MR, with an action that seems more predominant on the sensory rather on the motor component of the MR in a rat model of BHA associated with C-fibre afferent activation.

A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder.

OBJECTIVES: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor, UK-369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED). PATIENTS AND METHODS: This was a multicentre, double-blind, placebo-controlled, parallel-group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥ 18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥ 8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK-369,003; or placebo once a day) for 12 weeks. The primary study endpoints were those derived from the bladder diary that recorded the number of voluntary urinary voids, volume of urine per void, leaks and urgency episodes over a 72-h period, before baseline and again at 2, 4 and 12 weeks. Secondary efficacy measures included the International Prostate Symptom Score (total and storage and voiding subscores), International Index of Erectile Function-Erectile Function domain (IIEF-EF), questions 5 and 6 of the Quality of Erection Questionnaire (QEQ), the Overactive Bladder Questionnaire Short Form, the Patient Perception of Bladder Condition, the International Consultation on Incontinence Questionnaire-Male LUTS, and the patient-reported treatment impact questionnaire. RESULTS: Overall, there were no clinically relevant treatment differences in voiding frequency, mean voided volume, urgency episode frequency, or nocturia frequency for any dose of UK-369,003 MR compared with placebo. In the subset of patients with ED there were improvements in the IIEF-EF and QEQ scores in all UK-369,003 treatment groups compared with placebo. CONCLUSIONS: These data provide no evidence of efficacy for UK-369,003 in the treatment of storage LUTS in men (based on classic OAB eligibility criteria). However, although the endpoints on these classic OAB efficacy variables were negative, there is evidence to suggest a greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo.

Daily treatment with sildenafil reverses endothelial dysfunction and oxidative stress in an animal model of insulin resistance.

OBJECTIVES: Patients with insulin resistance exhibit endothelial dysfunction with decreased nitric oxide (NO) production and increased oxidative stress. We postulated that daily sildenafil improved endothelial function in fructose-fed rats. METHODS AND RESULTS: Wistar rats were fed a standard or fructose-enriched diet (FFR) for 9 wk. From weeks 6-8, sildenafil was administered twice daily (sc, 20 m g/kg), followed by a 1-wk washout. Concentration-response curves (CRCs) to endothelium-dependent (acetylcholine [Ach] and A23187) and -independent (sodium nitroprusside [SNP]) relaxing agents were performed on isolated precontracted aortas and superior mesenteric arteries (SMAs). Vascular cyclic guanosine monophosphate (cGMP) content, urinary excretion of nitrates/nitrites (NOx) and 8-isoprostanes (IPT), and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were evaluated. Relaxations to ACh were significantly reduced in aortas and SMAs of FFR. Sildenafil restored ACh-induced relaxations in aortas and provoked a significant leftward shift of the CRC to ACh in SMAs, whereas it did not modify the enhanced relaxations to SNP in FFR. IL-6, TNF-alpha, vascular cGMP, and urinary NOx levels were not modified by the fructose or sildenafil treatment. Urinary IPT levels were significantly elevated in FFR and normalized by sildenafil. CONCLUSIONS: Endothelial dysfunction and oxidative stress associated with insulin resistance can be reversed by daily sildenafil, even 1 wk after treatment cessation.

Comparison between tamsulosin and alfuzosin on the expulsion phase of ejaculation in rats.

OBJECTIVE: To investigate the effects of acute intravenous (i.v.) delivery of tamsulosin and alfuzosin on the contractions of bulbospongiosus muscles (BS) induced by central delivery of a serotonin agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in anaesthetized rats, as an experimental model of the expulsion phase of ejaculation. MATERIALS AND METHODS: Under urethane anaesthesia, adult male rats were implanted with a cannula into the lateral cerebral ventricle for intracerebroventricular (i.c.v.) injection, and with recording electrodes in the BS for electromyogram (EMG) monitoring. Tamsulosin (1 microg/kg) and alfusozin (10 microg/kg) were injected i.v. and 15 min later 8-OH-DPAT (20 microg) was delivered i.c.v. BS-EMG recording was continued for 30 min after i.c.v. 8-OH-DPAT. The area under the curve (AUC) of the BS cluster of contractions was determined as reflecting the energy of BS contractions. RESULTS: After i.c.v. delivery of 8-OH-DPAT, there were rhythmic BS contractions in the form of clusters of bursts in vehicle-, tamsulosin- and alfuzosin-treated rats. The number of BS clusters was not altered by the alpha1-blockers as compared with vehicle, but the AUC was significantly less in tamsulosin-treated rats than in vehicle- or alfuzosin-treated (both P < 0.05) rats. CONCLUSION: Systemic injection of tamsulosin impaired BS contractile capacity whereas alfuzosin did not. This might explain anejaculation in men treated with tamsulosin.

L6-S1 spinal nerve stimulation reduces micturition frequency in anaesthetized rats with cyclophosphamide-induced cystitis.

OBJECTIVE: To further investigate the rationale for using spinal nerve stimulation (SNS) for treating bladder overactivity associated with cystitis in a rat model of cyclophosphamide-induced cystitis, as several studies suggested that symptoms associated with chronic cystitis could be treated using stimulation of sacral spinal nerves, but the mechanisms by which it works are unknown. MATERIALS AND METHODS: Cystitis was induced by i.p. injection of cyclophosphamide 48 h before the experiments in anaesthetized male rats. Neurograms were taken by placing a recording electrode onto the pelvic nerve and a stimulating electrode on either the L6 or S1 ipsilateral spinal nerves. Two selected intensities were then evaluated for SNS in control and cyclophosphamide-treated rats during cystometry. RESULTS: Cyclophosphamide resulted in significant bladder overactivity. There was no apparent difference in the neurograms generated in response to SNS of the S1 and L6 spinal nerves, and between cyclophosphamide and control rats. Intensities of 200 microA (Adelta-fibre-specific) and 2 mA (Adelta+ C-fibres) were chosen for SNS. Continuous SNS at 200 microA significantly reduced the frequency of voiding and non-voiding contractions in cyclophosphamide-treated rats. SNS at 2 mA resulted in the abolition of voiding contractions, accompanied by continuous leakage of urine. CONCLUSION: SNS recruiting only Adelta-fibre produced fewer voiding contractions in cyclophosphamide-treated rats, to a level similar to that from the control rats. These results support the ability of SNS to decrease bladder overactivity in a pathophysiological model of chemical irritation of the bladder.

Prevalence of erectile dysfunction among 7689 patients with diabetes or hypertension, or both.

OBJECTIVES: To survey the presence of, and attitudes toward, erectile dysfunction (ED) among patients with hypertension and/or diabetes mellitus who sought general medical care for any reason. METHODS: The abbreviated five-item version of the International Index of Erectile Function (IIEF-5) was used to determine the presence of ED. A patient questionnaire was used to assess attitudes about ED. RESULTS: We surveyed 7689 patients (mean +/- SD age 58.9 +/- 9.2 years), including 6719 (87%) in a stable sexual relationship. In patients with hypertension alone (n = 3906) and diabetes alone (n = 2377), ED was reported by 2379 (61%) and 1603 (67%) and was present in 2634 (67%) and 1677 (71%), respectively, as defined by an IIEF-5 score of less than 21. The corresponding mean scores were 12.0 (+/-4.6) and 11.5 (+/-4.6) in patients with ED and 20.5 (+/-3.6) and 20.2 (+/-3.8) in those without ED. Prevalence was affected by disease characteristics and history, and the number and type of antihypertensive medications. ED was reported by 924 (78%) of 1186 patients with both diseases and was present in 917 (77%) according to the IIEF-5 score. Overall, ED was reported by 5063 patients (66%) with hypertension and/or diabetes, was present in 5391 (70%) according to the IIEF-5 score, and increased in prevalence with age. ED was fairly to very bothersome in 4027 (80%) but untreated in 3312 (65%), of whom 2278 (69%) wanted treatment. Most of those wanting treatment would have welcomed discussion with their physician (1861 [82%] of 2278), and most wanted their physician to broach the subject (1292 [69%] of 1861). CONCLUSIONS: Our study results have shown that patients with diabetes and/or hypertension have a high prevalence of bothersome untreated ED and want their general practitioner to initiate a discussion and provide treatment.