Stéphanie Caisey

Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord-injured rats.

BACKGROUND Phosphodiesterase type 5 inhibitors (PDE5-Is) improve storage symptoms in benign prostatic hyperplasia patients, despite a lack of effect on peak urinary flow rate. Moreover, vardenafil improves urodynamic parameters in spinal cord-injured (SCI) patients with neurogenic detrusor overactivity (NDO). SCI rats also display NDO characterized by nonvoiding contractions (NVCs) during bladder filling, resulting in an increased bladder afferent nerve firing (BANF). OBJECTIVE We postulated that vardenafil could improve urodynamic parameters by reducing BANF. The effect of vardenafil has been investigated on intravesical pressure by cystometry experiments while recording BANF in response to bladder filling. DESIGN, SETTING, AND PARTICIPANTS Complete T7-T8 spinalization was performed in 15 female adult Sprague-Dawley rats (250-275 g). MEASUREMENTS At 21-29 d postspinalization, fine filaments were dissected from the L6 dorsal roots and placed across a bipolar electrode. Bladder afferent nerve fibers were identified by electrical stimulation of the pelvic nerve and bladder distension. SCI rats were decerebrated before cystometry experiments. Bladders were filled to determine the maximal bladder filling volume (BFV) for each rat. Then, after bladder stabilization at 75% of maximal BFV, saline (n=7) or vardenafil 1 mg/kg (n=8) was delivered intravenously. NVCs and BANF were recorded for 45 min. RESULTS AND LIMITATIONS In all SCI rats, BANF was already present and regular at resting conditions (26.2±4.1 spikes per second). During bladder filling, intravesical pressure (IVP) slowly increased with transient NVCs superimposed. Concomitantly, BANF progressively increased up to 2.4-fold at maximal BFV (2.08±0.24 ml). After stabilization at submaximal BFV, BANF was increased by 186±37%. Vardenafil injection induced an immediate decrease in NVCs compared to saline (p<0.001) and BANF (52% decrease vs 28% in saline after 45 min; p<0.001). CONCLUSIONS Systemic vardenafil reduced both NVCs and BANF in unanesthetized, decerebrate, SCI rats. These findings provide new insights into the mechanism of action by which PDE5-Is improve storage symptoms in SCI patients.

Minimal effective dose of dysport and botox in a rat model of neurogenic detrusor overactivity.

BACKGROUND Two botulinum toxins A have been evaluated for the treatment of refractory neurogenic detrusor overactivity (NDO) in humans: Dysport (abobotulinumtoxinA) and Botox (onabotulinumtoxinA). However, these two distinct commercialized products have different potency units and are not interchangeable. OBJECTIVE Assessment of the dose response and determination of minimal effective dose (MED) for Dysport and Botox in spinal cord-injured (SCI) rats with NDO. DESIGN, SETTING, AND PARTICIPANTS Female, adult, Sprague-Dawley rats (n=98) underwent T8-T9 spinal cord transection. Nineteen days after spinal cord injury, rats received intradetrusor injections (25μl injected, eight sites) of vehicle (V); Dysport 2, 5, 7.5, 10, and 12.5 U; and Botox 0.8, 2, 5, 7.5, and 10 U. Two days after injection, continuous cystometry was performed in conscious rats. MEASUREMENTS Voiding contractions (VC) were assessed by duration of VC, intercontraction interval, voided volume, maximal pressure, pressure threshold change, and intravesical baseline pressure (BP), while nonvoiding contractions (NVC) were evaluated by amplitude, frequency, and volume threshold to elicit NVC. MEDs for Dysport and Botox were determined by analysis of variance step-down trend test. RESULTS AND LIMITATIONS MEDs for Dysport and Botox were 10 U and 7.5 U, respectively. Regarding VC, only BP significantly decreased after 10 U Dysport and 7.5 U Botox compared to V (from 3.7±0.6 to 1.5±0.1 and 1.4±0.3mm Hg, respectively; p<0.01 and p<0.001, respectively). Dysport (10 U) and Botox (7.5 U) significantly inhibited NVC by decreasing their amplitude (from 7.4±1.1 to 5.8±0.5 and 5.4±0.6mm Hg, respectively; p<0.05); frequency (from 2.2±0.4 to 1.5±0.2 and 1.3±0.3 NVC per minute, respectively; p<0.01); and increasing volume threshold to elicit NVC (from 29.8±3.7 to 47.6±6.9 and 47.7±6.3%, respectively; p<0.05 and p<0.001, respectively). CONCLUSIONS This is the first preclinical dose-ranging study with Dysport and Botox under standardized conditions showing similar inhibiting effects on NDO, albeit at different MEDs. It highlights the importance of distinguishing each preparation for predicted outcomes and doses to be used. Further studies in patients with NDO are warranted to confirm these experimental results.

A new experimental rat model of erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: the testosterone-supplemented spontaneously hypertensive rat

Whats known on the subject? and What does the study add?

Bladder and erectile dysfunctions in the Type 2 diabetic Goto-Kakizaki rat

Despite the fact that urogenito-sexual complications significantly impact the quality of life of diabetic patients, a robust in vivo experimental model is lacking. Bladder and erectile function in the Type 2 diabetic Goto-Kakizaki (GK) rat and responses to standard-of-care treatments for each disorder have been assessed. GK rats (n = 25, 18-wk-old, GK/Par colony) and age-matched Wistar rats (n = 23), characterized for their metabolic parameters, were used. Bladder function was assessed by cystometry in conscious rats treated by intravenous solifenacin (1 mg/kg). Subsequently, erectile function was assessed under anesthesia following electrical stimulation of the cavernous nerve in presence of intravenous sildenafil (0.3 mg/kg). GK rats displayed detrusor overactivity with a significant increase in frequency/amplitude of nonvoiding contractions during the filling phase, together with an increase in bladder capacity, intercontraction interval, voided volume, and maximal pressure of voiding contraction. Solifenacin significantly decreased parameters characterizing voiding contractions without modifying voiding efficiency. Erectile function in GK rats was markedly impaired and remained so after sildenafil treatment despite a significant improvement. GK rats display both bladder and erectile dysfunctions and respond at least partially to standard-of-care treatments for each disorder, thus representing a suitable model to investigate the pathophysiology and assess the efficacy of new therapeutic agents for Type 2 diabetes-associated bladder and erectile complications.

1005 VARDENAFIL DECREASES BLADDER AFFERENT NERVE FIRING IN UNANESTHETIZED DECEREBRATE SPINAL CORD-INJURED RATS

Background: Phosphodiesterase type 5 inhibitors (PDE5-Is) improve storage symptoms in benign prostatic hyperplasia patients, despite a lack of effect on peak urinary flow rate. Moreover, vardenafil improves urodynamic parameters in spinal cord-injured (SCI) patients with neurogenic detrusor overactivity (NDO). SCI rats also display NDO characterized by nonvoiding contractions (NVCs) during bladder filling, resulting in an increased bladder afferent nerve firing (BANF). Objective: We postulated that vardenafil could improve urodynamic parameters by reducing BANF. The effect of vardenafil has been investigated on intravesical pressure by cystometry experiments while recording BANF in response to bladder filling. Design, setting, and participants: Complete T7–T8 spinalization was performed in 15 female adult Sprague-Dawley rats (250–275 g). Measurements: At 21–29 d postspinalization, fine filaments were dissected from the L6 dorsal roots and placed across a bipolar electrode. Bladder afferent nerve fibers were identified by electrical stimulation of the pelvic nerve and bladder distension. SCI rats were decerebrated before cystometry experiments. Bladders were filled to determine the maximal bladder filling volume (BFV) for each rat. Then, after bladder stabilization at 75% of maximal BFV, saline (n = 7) or vardenafil 1 mg/kg (n = 8) was delivered intravenously. NVCs and BANF were recorded for 45 min. Results and limitations: In all SCI rats, BANF was already present and regular at resting conditions (26.2 4.1 spikes per second). During bladder filling, intravesical pressure (IVP) slowly increased with transient NVCs superimposed. Concomitantly, BANF progressively increased up to 2.4-fold at maximal BFV (2.08 0.24 ml). After stabilization at submaximal BFV, BANF was increased by 186 37%. Vardenafil injection induced an immediate decrease in NVCs compared to saline ( p < 0.001) and BANF (52% decrease vs 28% in saline after 45 min; p < 0.001). Conclusions: Systemic vardenafil reduced both NVCs and BANF in unanesthetized, decerebrate, SCI rats. These findings provide new insights into the mechanism of action by which PDE5-Is improve storage symptoms in SCI patients.

268 RHO-KINASE INHIBITION IMPACTS NEUROGENIC DETRUSOR OVERACTIVITY IN CHRONIC SPINALIZED RATS

Effect of Y-27632 on urodynamic parameters in consc ious SCI rats Spinal cord injury (SCI) severely disrupts normal bladder function by inducing neurogenic detrusor overactivity (NDO). First line SCIinduced NDO treatments i.e. antimuscarinics often associated with intermittent catheterization are somewhat limited by a mild to moderate clinical efficacy and a significant incidence of side effects. Thus the development of new effective drugs for the treatment of NDO is of crucial importance. Rho-kinase has a central role in the regulation of detrusor smooth muscle contraction since components of the rhoA/rho-kinase signalling pathway are involved in the Ca2+-sensitization of the smooth muscle 1. Moreover, in vitro and in vivo data from animal models of overactive bladder (OAB) indicate that rho-kinases are involved in pathophysiological mechanisms responsible for OAB 2,3. Thus, we aimed to evaluate the effects of a rho-kin ase inhibitor (Y-27632) on urodynamic parameters in rats with chronic SCI.

Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses endothelial dysfunction and oxidative stress associated with the metabolic syndrome

Materials and methods Wistar rats (n = 10–14 per group) were fed a standard chow (CONT) or a 60% fructose/5% fat (% by weight)enriched diet for 8 weeks (FFR). From week 5 through 8, sildenafil was administered twice a day (sc, 20 mg/kg, FFR+SIL), thus reaching clinically relevant plasma concentrations circa 20 nM unbound known to give efficacy in man (Pfizer Inc., data on file), then a 1-week wash-out period from sildenafil was observed. Isometric tension studies were performed on isolated aortic and superior mesenteric arterial (SMA) rings precontracted with noradrenaline to build concentration-response curves (CRC) to endothelium-dependent (ACh and A23187) and -independent (SNP) relaxants in presence of indomethacin. Urinary 8-isoprostanes (IPT) and plasma levels of IL-6 and TNF-α were also evaluated. Results Relaxations to ACh were reduced in aortas of FFR (10-5 M: -102.6 ± -2.4% vs -89.2 ± 4.7, p < 0.001) while only slightly affected in SMA rings. Relaxations to A23187 were significantly reduced both in aortic and SMA rings of FFR. In aortas, sildenafil treatment restored normal endothelium-dependent relaxations to ACh (10-5 M: -104.2 ± 3.0%, p < 0.001) even after one week of wash-out from treatment. In SMA rings, a leftward shift of the CRC to ACh could be detected (pD2: -8.12 ± 0.11 vs -8.60 ± 0.08, p < 0.05). Relaxations to A23187 were also restored by sildenafil in both aortic and SMA rings of FFR. Enhanced compensatory endothelium-independent relaxations to SNP in FFR were not modified by sildenafil treatment. Neither IL-6 nor TNF-α were modified by the fructose or sildenafil treatment. Urinary IPT levels was normalized by the sildenafil treatment (FFR: 2.07 ± 0.36 vs CONT:0.95 ± 0.14 vs FFR+SIL: 0.88 ± 0.13 ng/ml/24 h, p < 0.05).