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To compare the dose effect relationship of a selective β3 -adrenoceptor agonist (CL-316,243) on cystometric parameters in anesthetized and conscious rats and to evaluate its effect in a model of neurogenic bladder overactivity induced by spinal cord injury (SCI).Experiments were performed in anesthetized and conscious normal rats and in conscious rats after complete transection at the T8 level of the spinal cord. The jugular vein and urinary bladder were catheterized and the bladder infused with saline. CL-316,243 was tested intravenously at 0.01, 0.03, and 0.1 mg/kg in anesthetized and conscious rats and at 0.01 mg/kg in sham and SCI rats. Intravesical pressure was recorded for 1 hr following drug administration. Intercontraction interval (ICI), amplitude of micturition (AM), micturition frequency (MF) and non-voiding contractions (NVC) were analyzed.In anesthetized and conscious normal rats, CL-316,243 significantly increased ICI in a dose-dependent manner. In anesthetized rats, AM was significantly decreased at all doses tested whereas in conscious rats, a significant decrease (-19 ± 6%) in AM was only observed at the highest dose (0.1 mg/kg). In conscious sham and SCI rats, CL-316,243 significantly increased ICI (42 ± 17% and 49 ± 17%, respectively) and decreased MF without affecting AM. In SCI rats, CL-316,243 reduced the frequency of NVC (-53 ± 14%) without significant effects on amplitude.The current results suggest that anesthesia can alter the effects of β3 -adrenoceptor agonists in experimental models. In addition, this is the first demonstration that stimulation of β3 -adrenoceptors can produce decreases in micturition frequency and NVC in SCI rats without affecting AM.

The GABAB receptor agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen's side effects limit its use for the treatment of overactive bladder (OAB). Here, we tested a novel GABAB positive allosteric modulator (PAM) ADX71441 in models of OAB in mice and guinea pigs.Mice were left untreated or given (p.o.) vehicle (1% CMC), ADX71441 (1, 3, 10 mg kg(-1) ) or oxybutynin (100 mg kg(-1) ; Experiment 1) or vehicle (1% CMC), baclofen (1, 3, 6 mg kg(-1) ) or oxybutynin (Experiment 2). Treated mice were then overhydrated with water, challenged with furosemide, before being placed into micturition chambers and monitored for urinary parameters. In anaesthetized guinea pigs, intravesical infusion of acetic acid was used to induce OAB and the effects of ADX71441 (1, 3 mg kg(-1) ) or baclofen (1 mg kg(-1) ), administered i.v., on cystometric parameters were monitored.In mice, 10 mg kg(-1) ADX71441 increased urinary latencies, reduced the number of urinary events and the total and average urinary volumes. In guinea pigs, ADX71441 (1 and 3 mg kg(-1) ) increased the intercontraction interval (ICI) and bladder capacity (BC), and reduced micturition frequency (MF) compared to vehicle. At 3 mg kg(-1) ADX71441 completely inhibited the micturition reflex and induced overflow incontinence in five out of 10 animals. Baclofen slightly increased ICI and BC and reduced MF.Our findings demonstrate, for the first time, that a GABAB PAM has potential as a novel approach for the treatment of OAB.

To compare the direct relaxant effects of alfuzosin, phentolamine and sildenafil in rabbit isolated corpus cavernosum (CC) pre-contracted with phenylephrine or KCl.Penile erectile tissue was obtained from male New Zealand White rabbits (22-26 weeks old). The CC was cut into longitudinal strips and mounted under 2 g resting tension in 5-mL jacketed organ baths containing a modified Krebs solution bubbled with 95% O2, 5% CO2 and maintained at 37 degrees C. Tissue strips were pre-contracted by 60 mmol/L KCl or 10 micro mol/L phenylephrine. After obtaining a stable plateau of contractions, test compounds were added to the organ bath. The relaxant potencies were expressed as the percentage of inhibition of the plateau of contraction induced by 10 micro mol/L phenylephrine.Alfuzosin showed a concentration-dependent relaxing effect on rabbit CC pre-contracted by 10 micro mol/L phenylephrine, with a mean (sd) pIC50 of 7.64 (0.06). The relaxant effect was unaffected by pre-incubation with 100 micro mol/L Nomega-nitro-l-arginine methyl ester (L-NAME). Phentolamine had a potency similar to alfuzosin, with a pIC50 of 7.44 (0.08). Both alfuzosin and phentolamine were completely ineffective on the plateau of contraction induced by 60 mmol/L KCl. In contrast to alfuzosin, sildenafil was equipotent in relaxing the rabbit CC against each contractile agent, with pIC50 values of 7.25 (0.09) and 7.23 (0.22) with 10 micro mol/L phenylephrine and 60 mmol/L KCl, respectively. The relaxant response to sildenafil was partly blocked by pretreatment with 100 micro mol/L L-NAME, with pIC50 values of 7.94 (0.09) and 6.63 (0.32) without and with L-NAME, respectively. Sildenafil, incubated for 45 min at 10 micro mol/L, had no relaxant effect on the resting tension of the preparation or on the concentration-response curve to phenylephrine.The direct relaxant effect of alfuzosin is mediated through alpha1-adrenoceptor blockade. The relaxations induced by phentolamine and alfuzosin are independent of nitric oxide, whereas those induced by sildenafil are, at least partly, sensitive to L-NAME and a selective soluble guanylate cyclase inhibitor, indicating the involvement of nitric oxide and soluble guanylate cyclase. Alfuzosin and phentolamine effectively counteract alpha1-adrenoceptor-mediated contractions of rabbit CC. If valid for human CC, such an effect may contribute to an improved erectile function in patients treated for benign prostatic hyperplasia.

To investigate the changes in bladder function after multiple pregnancies and parturition in rats, and to establish links between the changes in voiding profiles and in vitro pharmacological responses.Cystometry was used in conscious virgin and multiparous female Wistar rats (2 weeks after the last parturition) with chronically implanted lines to continuously record bladder pressure during five reproducible voiding cycles. In vitro, detrusor muscle contractile responses induced by cumulative concentrations of KCl, carbachol, noradrenaline and alpha, beta-methylene-ATP (mATP) were compared.In multiparous rats, there was a significant increase in the amplitude of voiding pressure (+31%), bladder capacity (+83%) and residual volume (about threefold); 60% of the multiparous rats but only 10% of the virgin rats showed bladder instability during the filling phase. Cumulative concentration-response curves to KCl, expressed as the tension developed vs tissue weight, were identical in the two groups of rats. Contractile responses induced by carbachol (0.1-30 micromol/L) were significantly larger in multiparous than in virgin rats. Similarly, noradrenaline-induced contractions (0.3-10 micromol/L) were significantly higher for multiparous animals. However, the sensitivity of the detrusor muscle to mATP was not modified by multiple pregnancies.After multiple gestations, female rats develop bladder hypertrophy, bladder instabilities and a higher amplitude of voiding pressure associated with an increased residual volume. These altered patterns are similar to those found in rats after chronic infravesical outlet obstruction. We propose that pregnancies and parturition modify urinary bladder function, leading to a dysfunction similar to that induced by obstruction, and involving an increased sensitivity to adrenergic and cholinergic stimulation.

The aim of this work was to study the role of capsaicin-sensitive afferent fibers in modulating the micturition reflex at spinal level in urethane-anesthetized guinea pigs after spinal cord transection at level T3-T4.The intravesical effect of capsaicin was investigated in a series of cystometrograms performed in intact and spinalized animals.In both intact and spinalized animals capsaicin, at 30 microM, induced a significant increase of volume threshold only, whereas at 100 microM it induced a complete inhibition of the spinal micturition reflex in 60% and 85% of the animals tested, respectively. This capsaicin inhibitory effect (CIE) was unaffected by intravenous phentolamine and propranolol (0.5 and 1 mg./kg., respectively), indomethacin at 100 nmoles intrathecally (i.t.), the CGRP receptor antagonist hCGRP8-37 (3 nmoles i.t.) and the NK2 receptor selective antagonist GR 94800 (1 nmol. i.t.). However, both naloxone (30 microg. i.t.) and the NK1 antagonist GR 82334 (10 to 20 nmoles i.t.) prevented CIE in the majority of spinalized animals.These results suggest that CIE could be mediated by enkephalines released by dorsal root ganglion neurons through substance P release and subsequent activation of NK1 receptors in acutely spinalized guinea pigs.

The activity of a selective cholecystokinin (CCK)-A receptor agonist, N-acetyl derivative of A71623 (Ac-Trp-Lys(epsilon-N-[2-methylphenylamino-carbonyl]) -Asp-(NMe)Phe-NH2) was investigated in the guinea pig isolated ileum longitudinal muscle myenteric plexus. NAA caused both a phasic and tonic contraction at all concentrations tested (1-1000 nM). The selective CCK-A antagonist L-364,718 (Devazepide) antagonized both types of contraction with a pKB of 10.10 and 9.95, respectively. The CCK-B selective antagonist L-365,260 ((3R(+)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3yl)-N-(3-methylphenyl)-urea) was inactive up to a concentration of 30 nM. Atropine at 300 nM and 1000 nM reduced the maximal response of NAA by only 17% and 50%, respectively. The selective neurokinin (NK)-1 antagonists GR 82334 ([D-pro9[Spiro-gamma-Lactam] Leu10, Trp11]-Phys (1-11)9) at 300 and 1000 nM and (+-) CP-96,345 [(2S, 3S)-cis- 2-(diphenylmethyl)-N- [(2-methoxyphenyl)-methyl] -1-azabici-clo [2.2.2]octan-3-amine] at 10 nM were inactive or partially active. When atropine and GR 82334 or (+/-) CP-96,345 were combined, they produced a dose-dependent synergistic inhibition of both phasic and tonic contractions induced by NAA. The selective NK-3 receptor agonist senktide induced both phasic and tonic contractions that were blocked by tetrodotoxin. In the presence of atropine and GR 82334, both 300 nM, a synergistic depression of the response to senktide similar to that observed for the agonist NAA was disclosed.(ABSTRACT TRUNCATED AT 250 WORDS)