endothelin-1 and Urinary-Bladder--Overactive

Mirabegron is used for treatment of storage symptoms in overactive bladder (OAB) caused by spontaneous bladder smooth muscle contractions. However, owing to limitations in available studies using human tissues, central questions are still unresolved, including mechanisms underlying improvements by mirabegron and its anticontractile effects in the detrusor. Here, we assessed concentration-dependent mirabegron effects on contractions of human detrusor tissues in frequency-response curves and concentration-response curves for different cholinergic and noncholinergic agonists. Detrusor tissues were sampled from patients undergoing radical cystectomy. Contractions were induced by electric field stimulation (EFS) and by cumulative concentrations of cholinergic agonists, endothelin-1, and the thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetanilides; Carbachol; Endothelin-1; Female; Humans; Male; Methacholine Chloride; Muscle Contraction; Muscle, Smooth; Receptors, Adrenergic; Thiazoles; Urinary Bladder, Overactive

OBJECTIVE To investigate the in vitro and in vivo effects of blebbistatin (a small cell-permeable molecule with high affinity and selectivity toward the myosin II contractile molecule) on bladder smooth muscle (SM) contractility, as antimuscarinic therapy is only 65-75% effective in treating overactive bladder (OAB) and is associated with considerable side-effects, with a < 25% continuation rate at 1 year. MATERIALS AND METHODS Bladder and aortic strips from adult male rats, and human bladder strips obtained from open prostatectomy, were used for organ-bath studies of blebbistatin. Awake cystometry was also used in rats in both the presence and absence of intravesically delivered blebbistatin. RESULTS Blebbistatin dose-dependently and completely relaxed both KCl- and carbachol-induced rat detrusor and endothelin-1-induced human bladder contraction. Pre-incubation with 10 µm blebbistatin attenuated carbachol responsiveness by ≈ 65% while blocking electrical field stimulation-induced bladder contraction reaching 50% inhibition at 32 Hz. The basal tone and amplitude of spontaneous contraction were also significantly diminished. Urodynamic variables were obviously altered by intravesical infusion with blebbistatin. CONCLUSION Our novel data show that blebbistatin strongly relaxes both rat and human bladder contraction induced by various physiological stimuli. Coupled with our in vivo data showing that nanomole doses of blebbistatin significantly alter urodynamic variables to produce a less active bladder, our results suggest the possibility of intravesically administered blebbistatin binding at myosin II being developed as a therapeutic treatment for OAB via a novel targeting of the SM contractile apparatus.

Topics: Animals; Endothelin-1; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Muscle Contraction; Muscle, Smooth; Myosin Type II; Parasympatholytics; Rats; Rats, Sprague-Dawley; Urinary Bladder; Urinary Bladder, Overactive

Recently, growing clinical evidence has suggested that sexual dysfunction is more prevalent in women with overactive bladder (OAB). Aims. However, there has been no basic research to clarify the relationship between OAB and female sexual dysfunction. Therefore, we investigated this issue using a rabbit model of OAB.. Twenty-seven New Zealand white female rabbits were randomly divided into the OAB and control groups.. The contractile responses of clitoral cavernous strips to K(+), phenylephrine (PE), Bay K 8644, and endothelin (ET)-1, and the relaxation responses of acetylcholine (ACh), sodium nitroprusside (SNP), and Y-27632 to PE-induced contraction by measuring isometric tension. Results. The contractile responses to K(+), PE, Bay K 8644, and ET-1 were significantly more increased in the OAB group in a dose-dependant manner than in the control group (P < 0.05), and the responses to ET-1 were more prominent than those to the remaining substances (P < 0.01). The increased contractile responses to ET-1 were blocked by BQ123 (ET(A) receptor antagonist) but not by BQ788 (ET(B) receptor antagonist). Clitoral cavernosal strips from the OAB group were more difficult to relax than those from the control group in terms of ACh- and SNP-induced relaxation (P < 0.05). The Y-27632-induced relaxant responses to PE- and ET-1-induced contraction were less prominent in the OAB group than in the control group. CONCLUSIONS; The results of this study provide evidence that female OAB may deteriorate clitoral engorgement, which is associated with a greater force generation by increased calcium sensitization and subsequently decreased of relaxation. The activation of ET and Rho-kinase system may be crucial to negatively effect the clitoral smooth muscle relaxation in experimentally induced OAB animal model. But whether these vasomotor effects are revived in human clitoris is still debatable.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Acetylcholine; Adrenergic alpha-Agonists; Amides; Animals; Antihypertensive Agents; Calcium Channel Agonists; Clitoris; Dose-Response Relationship, Drug; Endothelin-1; Female; Isometric Contraction; Models, Animal; Muscle Relaxants, Central; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Oligopeptides; Peptides, Cyclic; Phenylephrine; Piperidines; Potassium; Pyridines; Rabbits; Urinary Bladder, Overactive; Vasodilator Agents