ABSTRACT
The clinical success of mirabegron as the first β₃-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β₃-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β₃-AR stimulation have still not been established. The recent demonstration of β₃-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β₃-ARs can be found these structures. However, recent studies suggest that the β₃-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β₃-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.
Subject(s)
Acetylcholine , Lower Urinary Tract Symptoms , Muscle, Smooth , Neurons , Relaxation , Urethra , Urinary Bladder , Urinary Bladder, Overactive , UrotheliumABSTRACT
Objectives: To investigate the effect of warming on contraction of the detrusor muscle and the micturition reflex in rats. Methods: Female Sprague-Dawley rats were used in this study. Changes in the contractile response of detrusor smooth muscle strips to 40 mM KCl caused by warming to 40°C and 42°C were evaluated by an isometric tension recording study. The effect of intravesical warming at 40.7±1.0°C on the micturition reflex was evaluated by continuous infusion cystometry in conscious rats. Results: Warming to 40°C and 42°C inhibited 40 mM KCl-induced contractions of detrusor smooth muscle strips by 10% and 15.5%, respectively. Intravesical warming at 40.7±1.0°C decreased the pressure threshold for inducing micturition by 14%, resting pressure by 30%, closing peak pressure by 22%, 2nd phase contraction duration by 36%, bladder contraction duration by 26%, and increased bladder compliance by 17%. Maximal voiding pressure and 1st phase contraction duration were unaltered. Conclusions: Our results demonstrated that warming relaxed the detrusor muscle and increased bladder compliance. This suggests that warming might be useful for treatment of low compliance bladder observed in the neurogenic bladder due to neurological diseases such as spinal cord injury. To clarify the usefulness of warming or hot springs for the treatment of neurogenic bladder, the effect of warming on the body surface on the micturition reflex should be investigated.
ABSTRACT
<b>Objectives:</b> To investigate the effect of warming on contraction of the detrusor muscle and the micturition reflex in rats.<BR><b>Methods:</b> Female Sprague-Dawley rats were used in this study. Changes in the contractile response of detrusor smooth muscle strips to 40 mM KCl caused by warming to 40°C and 42°C were evaluated by an isometric tension recording study. The effect of intravesical warming at 40.7±1.0°C on the micturition reflex was evaluated by continuous infusion cystometry in conscious rats.<BR><b>Results:</b> Warming to 40°C and 42°C inhibited 40 mM KCl-induced contractions of detrusor smooth muscle strips by 10% and 15.5%, respectively. Intravesical warming at 40.7±1.0°C decreased the pressure threshold for inducing micturition by 14%, resting pressure by 30%, closing peak pressure by 22%, 2nd phase contraction duration by 36%, bladder contraction duration by 26%, and increased bladder compliance by 17%. Maximal voiding pressure and 1st phase contraction duration were unaltered.<BR><b>Conclusions:</b> Our results demonstrated that warming relaxed the detrusor muscle and increased bladder compliance. This suggests that warming might be useful for treatment of low compliance bladder observed in the neurogenic bladder due to neurological diseases such as spinal cord injury. To clarify the usefulness of warming or hot springs for the treatment of neurogenic bladder, the effect of warming on the body surface on the micturition reflex should be investigated.
ABSTRACT
Background: Ischuria is a health and social problem, having a negative impact on sufferers. This study therefore was a preliminary investigation of the ischuretic property and safety for use of a hydro-ethanolic extract of Amaranthus spinosus used traditionally in managing ischuria. Methods: Phytochemical screening, thin layer chromatography and high performance liquid chromatography were performed on the extract to establish fingerprints for identification. Acetylcholine, Nicotine, and the extract were applied to an isolated rat urinary bladder to ascertain contractile response. The possible receptor site(s) of action was also investigated using isolated rabbit jejunum, and guinea-pig ileum preparations. In-house observation, hematological analysis, and liver and kidney function tests were performed on Sprague-Dawley rats, in acute and sub-acute toxicity studies. Results: The extract had contractile effects on the rat urinary bladder (similar to acetylcholine and nicotine) and rabbit jejunum. Its contractile effect of the guinea-pig ileum was significantly inhibited by hexamethonium (77.50 ± 8.50 %; P ≤ 0.001) and to a lesser extent by mepyramine (49.2 ± 6.80 %; P ≤ 0.001) and Atropine (22.45 ± 5.22 %; P ≤ 0.01). The extract (80-800 mg kg-1) was not lethal and a 160 and 240 mg kg-1 dose had no adverse effect on blood, liver, kidney metabolic function. Conclusions: The hydro-ethanolic extract of Amaranthus spinosus has ischuretic activity possibly mediated via nicotinic, histaminic and muscarinic receptor stimulation and is safety to use in ischuria.
ABSTRACT
Defensins, cysteine-rich cationic polypeptides released from neutrophils, are known to have powerful antimicrobial properties. In this study, we sacrificed 30 rats to investigate the effects of alpha-defensin 1 on detrusor muscle contractions in isolated rat bladder. From the experiments we found relaxing effects of alpha-defensin 1 on the contractions induced by phenylephrine (PE) but not by bethanechol (BCh) in the detrusor smooth muscles. To determine the mechanisms of the effects of alpha-defensin 1, the changes of effects on PE-induced contraction by alpha-defensin 1 pretreatment were observed after pretreatment of Rho kinase inhibitor (Y-27632), protein kinase C (PKC) inhibitor (Calphostin C), potent activator of PKC (PDBu; phorbol 12,13-dibutyrate), and NF-kappaB inhibitors (PDTC; pyrrolidinedithiocarbamate and sulfasalazine). The contractile responses of PE (10(-9) ~ 10(-4) M) were significantly decreased in some concentrations of alpha-defensin 1 (5x10(-9) and 5x10(-8) M). When strips were pretreated with NF-kappaB inhibitors (PDTC and sulfasalazine; 10(-7) ~ 10(-6) M), the relaxing responses by alpha-defensin 1 pretreatment were disappeared. The present study demonstrated that alpha-defensin 1 has relaxing effects on the contractions of rat detrusor muscles, through NF-kappaB pathway. Further studies in vivo are required to clarify whether alpha-defensin 1 might be clinically related with bladder dysfunction by inflammation process.
Subject(s)
Animals , Rats , Bethanechol , Contracts , Defensins , Inflammation , Muscle Contraction , Muscle, Smooth , Muscles , Neutrophils , NF-kappa B , Peptides , Phenylephrine , Phorbols , Protein Kinase C , Pyrrolidines , rho-Associated Kinases , Thiocarbamates , Urinary BladderABSTRACT
Considerable advances have been made in the understanding of the cellular processes that result in contraction and relaxation of detrusor smooth muscle recently,particularly in the role and modulation of calcium.Several changes in these cellular mechanisms that impair normal function have been observed in detrusor muscle from patients with unstable bladders.Whether these changes represent primary causes of bladder dysfunction or whether they are secondary to bladder dysfunction remains to be determined.Nevertheless,the identification of specific cellular lesions in bladder dysfunction presents a novel approach to identification of drug targets and potential treatment modalities.
ABSTRACT
Objective To investigate the role of Ca 2+ signaling in the overexpression of detrusor smooth muscle cell connexin 43 by cyclic stretch in vitro. Methods The detrusor smooth muscle cells (DSMC) grown on collagen-coated silicone membranes were subjected to cyclic stretch-relaxation. The Cx43 mRNA in DSMC were detected with RT-PCR, and the concentration of intracellular free Ca 2+ in DSMC was measured by confocal microscopy in conjunction with the calcium indicator, Fura-3 (Molecular Probes). Results The overexpression of Cx43 mRNA induced by cyclic stretch was significantly inhibited by EGTA.The increase of intracellular free Ca 2+ induced by stretch was also inhibited completely by EGTA, 61.95% by GdCl3, 29.98% by Nifedipine, 87.98% by Ryanodine and Thapsigargin. Conclusion The stretch-induced Ca 2+ entry, via the Ca 2+-induced Ca 2+ release mechanism, may play an important role in DSMC connexin 43 overexpression induced by cyclic stretch.