cl-316243 and Urinary-Bladder--Overactive

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.

Topics: Adrenergic beta-3 Receptor Agonists; Anesthesia; Animals; Consciousness; Dioxoles; Dose-Response Relationship, Drug; Female; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Urinary Bladder; Urinary Bladder, Overactive; Urination; Urodynamics

To investigate pathways involving beta-3 adrenergic receptors (ARs) in detrusor overactivity induced by cold stress, we determined if the beta-3 AR agonist CL316243 could modulate the cold stress-induced detrusor overactivity in normal rats.. Two days prior to cystometric investigations, the bladders of 10-week-old female Sprague-Dawley rats were cannulated. Cystometric measurements of the unanesthetized, unrestricted rats were taken to estimate baseline values at room temperature (RT, 27 ± 2 °C) for 20 min. They were then intravenously administered vehicle, 0.1, or 1.0 mg/kg CL316243 (n = 6 in each group). Five minutes after the treatments, they were gently and quickly transferred to the low temperature (LT, 4 ± 2 °C) room for 40 min where the cystometric measurements were again made. Afterward, the rats were returned to RT for final cystometric measurements. The cystometric effects of CL316243 were also measured at RT (n = 6 in each group).. At RT, both low and high dose of CL316243 decreased basal and micturition pressure while the high dose (1.0 mg/kg) significantly increased voiding interval and bladder capacity. During LT exposure, the high dose of CL316243 partially reduced cold stress-induced detrusor overactivity characterized by increased basal pressure and urinary frequency. The high drug dose also significantly inhibited the decreases of both voiding interval and bladder capacity compared to the vehicle- and low dose (0.1 mg/kg)-treated rats.. A high dose of the beta-3 agonist CL316243 could modulate cold stress-induced detrusor overactivity. Therefore, one of the mechanisms in cold stress-induced detrusor overactivity includes a pathway involving beta-3 ARs.

Topics: Adrenergic beta-3 Receptor Agonists; Animals; Biomarkers; Cold Temperature; Consciousness; Dioxoles; Dose-Response Relationship, Drug; Female; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-3; Stress, Physiological; Urinary Bladder, Overactive

β3-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β3-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β2-selective fenoterol and the β3-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β2 component of rat bladder relaxation but much weaker or even absent for the β3 component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β3-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Carbachol; Dioxoles; Fenoterol; Isoproterenol; Male; Muscarinic Agonists; Muscle Contraction; Muscle Relaxation; Potassium Chloride; Rats; Rats, Wistar; Urinary Bladder; Urinary Bladder, Overactive

To examine the relaxant effects of AJ-9677, a novel beta(3)-adrenoceptor agonist, on the isolated rat, monkey and human detrusor muscle.. The isolated detrusor strips of rats, monkeys and humans were mounted in organ baths containing Krebs solution. By the cumulative addition of beta-adrenoceptor agonists (isoproterenol, AJ-9677, CL 316,243 and salbutamol in rats; isoproterenol, AJ-9677 and CL 316,243 in monkeys and humans), concentration-relaxation curves were obtained. The maximal relaxation responses and pEC(50) values were calculated. In rats, concentration-relaxation curves to isoproterenol and AJ-9677 were obtained in the presence and absence of propranolol or SR 59230A.. Isoproterenol, AJ-9677, CL 316,243 and salbutamol induced concentration-dependent relaxation in rats. The rank order of their relaxing potency in the rat detrusor muscle was AJ-9677 > isoproterenol > CL 316,243 > salbutamol. Isoproterenol and AJ-9677 also produced a concentration-dependent relaxation with high potency in monkeys and humans, whilst CL 316,243 had low relaxing potency. According to the antagonist studies in rats, propranolol and SR 59230A caused a rightward shift of the concentration-relaxation curves to isoproterenol or AJ-9677, respectively.. AJ-9677 has a high relaxant potency on the rat, monkey and human detrusor smooth muscle, and it may have the potential to treat overactive bladder.

Topics: Acetates; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Animals; Dioxoles; Female; Humans; In Vitro Techniques; Indoles; Isoproterenol; Macaca fascicularis; Male; Middle Aged; Muscle Relaxation; Muscle, Smooth; Propanolamines; Propranolol; Rats; Rats, Sprague-Dawley; Urinary Bladder, Overactive

The present study investigated whether beta3-adrenoceptor activation acts on the bladder afferent pathway by examination of the visceromotor reflex (VMR) and pressor responses to urinary bladder distension (UBD) and whether beta3-adrenoceptor activation produces urinary bladder relaxation in hyperactive spontaneously hypertensive rats (SHRs) in comparison with their normotensive control rats [Wistar-Kyoto (WKY)]. Using the VMR responses to noxious UBD as a measure of bladder afferent signal transmission, SHRs did not present a sensitized bladder phenotype. However, reduced bladder compliance accompanied by a reduced void threshold was detected in the SHR detrusor. Furthermore, the selective beta3-adrenoceptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) (i.v.) failed to attenuate VMR or pressor responses to UBD in either SHRs or WKY rats, but it dose-dependently inhibited rhythmic contraction (RC) in SHRs. The minimal effective dose was 0.001 mg/kg. Using the same model in WKY rats, CL-316243 did not elicit significant inhibition of contractions in the bladder RC assay. These results suggest that SHRs represent abnormal efferent/detrusor function (detrusor overactivity) without mechanosensory afferent hypersensitivity. The beta3-adrenoceptor agonist CL-316243 acts on the detrusor muscle to increase urine storage in SHRs.

Topics: Adrenergic beta-3 Receptor Agonists; Animals; Dioxoles; Female; Muscle Contraction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, beta-3; Urinary Bladder; Urinary Bladder, Overactive; Urination