scholarly journals Urothelium-Specific Deletion of Connexin43 in the Mouse Urinary Bladder Alters Distension-Induced ATP Release and Voiding Behavior

2021 ◽  
Vol 22 (4) ◽  
pp. 1594
Author(s):  
Jin Kono ◽  
Masakatsu Ueda ◽  
Atsushi Sengiku ◽  
Sylvia O. Suadicani ◽  
Osamu Ogawa ◽  
...  
Keyword(s):  
Urinary Bladder ◽  
Atp Release ◽  
Active Phase ◽  
Bladder Capacity ◽  
Wild Type ◽  
Sleep Phase ◽  
Cx43 Expression ◽  
Bladder Distention ◽  
Atp Signaling ◽  
Specific Deletion

Connexin43 (Cx43), the main gap junction and hemichannel forming protein in the urinary bladder, participates in the regulation of bladder motor and sensory functions and has been reported as an important modulator of day–night variations in functional bladder capacity. However, because Cx43 is expressed throughout the bladder, the actual role played by the detrusor and the urothelial Cx43 is still unknown. For this purpose, we generated urothelium-specific Cx43 knockout (uCx43KO) mice using Cre-LoxP system. We evaluated the day–night micturition pattern and the urothelial Cx43 hemichannel function of the uCx43KO mice by measuring luminal ATP release after bladder distention. In wild-type (WT) mice, distention-induced ATP release was elevated, and functional bladder capacity was decreased in the animals’ active phase (nighttime) when Cx43 expression was also high compared to levels measured in the sleep phase (daytime). These day–night differences in urothelial ATP release and functional bladder capacity were attenuated in uCx43KO mice that, in the active phase, displayed lower ATP release and higher functional bladder capacity than WT mice. These findings indicate that urothelial Cx43 mediated ATP signaling and coordination of urothelial activity are essential for proper perception and regulation of responses to bladder distension in the animals’ awake, active phase.

scholarly journals Serotonergic regulation of distention-induced ATP release from the urothelium

2016 ◽  
Vol 310 (7) ◽  
pp. F646-F655 ◽  
Author(s):  
Kazumasa Matsumoto-Miyai ◽  
Erika Yamada ◽  
Eriko Shinzawa ◽  
Yoshihisa Koyama ◽  
Shoichi Shimada ◽  
...  
Keyword(s):  
Urinary Bladder ◽  
Tryptophan Hydroxylase ◽  
Atp Release ◽  
Pcr Amplification ◽  
Inhibitory Effect ◽  
Visceral Sensation ◽  
Rt Pcr ◽  
Specific Expression ◽  
Bladder Distention ◽  
Gr 127935

Serotonin [5-hydroxytryptamine (5-HT)] is involved in both motor and sensory functions in hollow organs, especially in the gastrointestinal tract. However, the involvement of 5-HT in visceral sensation of the urinary bladder remains unknown. Because distention-induced ATP release from the urothelium plays an essential role in visceral sensation of the urinary bladder, we investigated the regulation of urothelial ATP release by the 5-HT signaling system. RT-PCR and immunohistochemical analyses of the urothelium revealed specific expression of 5-HT1D and 5-HT4 receptors. The addition of 5-HT did not affect urothelial ATP release without bladder distention, but it significantly reduced distention-induced ATP release by physiological pressure during urine storage (5 cmH2O). The inhibitory effect of 5-HT on distention-elicited ATP release was blocked by preincubation with the 5-HT1B/1D antagonist GR-127935 but not by the 5-HT4 antagonist SB-204070. mRNA encoding tryptophan hydroxylase 1 was detected in the urinary bladder by nested RT-PCR amplification, and l-tryptophan or the selective serotonin reuptake inhibitor citalopram also inhibited ATP release, indicating that 5-HT is endogenously synthesized and released in the urinary bladder. The addition of GR-127935 significantly enhanced the distention-elicited ATP release 40 min after distention, whereas SB-204070 reduced the amount of ATP release 20 min after distention. These data suggest that 5-HT4 facilitates the distention-induced ATP release at an earlier stage, whereas 5-HT1D inhibits ATP release at a later stage. The net inhibitory effect of 5-HT indicates that the action of 5-HT on the urothelium is mediated predominantly by 5-HT1D.

scholarly journals Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Francie Moehring ◽  
Ashley M Cowie ◽  
Anthony D Menzel ◽  
Andy D Weyer ◽  
Michael Grzybowski ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Ex Vivo ◽  
Atp Release ◽  
Mechanical Sensitivity ◽  
Tactile Stimuli ◽  
P2x4 Receptors ◽  
Touch Sensation ◽  
Atp Signaling ◽  
Specific Deletion

The first point of our body’s contact with tactile stimuli (innocuous and noxious) is the epidermis, the outermost layer of skin that is largely composed of keratinocytes. Here, we sought to define the role that keratinocytes play in touch sensation in vivo and ex vivo. We show that optogenetic inhibition of keratinocytes decreases behavioral and cellular mechanosensitivity. These processes are inherently mediated by ATP signaling, as demonstrated by complementary cutaneous ATP release and degradation experiments. Specific deletion of P2X4 receptors in sensory neurons markedly decreases behavioral and primary afferent mechanical sensitivity, thus positioning keratinocyte-released ATP to sensory neuron P2X4 signaling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signaling that occurs in cutaneous pain and itch disorders, and ultimately, the development of novel topical therapeutics for these conditions.

Enhanced bladder capacity and reduced prostaglandin E2-mediated bladder hyperactivity in EP3 receptor knockout mice

2008 ◽  
Vol 295 (2) ◽  
pp. F507-F514 ◽  
Author(s):  
Gerald P. McCafferty ◽  
Blake A. Misajet ◽  
Nicholas J. Laping ◽  
Richard M. Edwards ◽  
Kevin S. Thorneloe
Keyword(s):  
Urinary Bladder ◽  
Potential Role ◽  
Bladder Capacity ◽  
Bladder Function ◽  
Cyclooxygenase Inhibitors ◽  
Prostaglandin E ◽  
Wild Type ◽  
Pathological Conditions ◽  
Freely Moving ◽  
Ep3 Receptor

Nonsteroidal anti-inflammatory cyclooxygenase inhibitors that function to reduce prostaglandin E2 (PGE2) production have been widely reported as effective agents in models of urinary bladder overactivity. We therefore investigated a potential role for the PGE2 receptor, EP3, in urinary bladder function by performing conscious, freely moving cystometry on EP3 receptor knockout (KO) mice. EP3 KO mice demonstrated an enhanced bladder capacity compared with wild-type (WT) mice (∼185% of WT) under control conditions, based on larger voided and infused bladder volumes. Infusion of the EP3 receptor agonist GR63799X into the bladder of WT mice reduced the bladder capacity. This was ineffective in EP3 KO mice that demonstrated a time-dependent increase in bladder capacity with GR63799X, an effect similar to that observed with vehicle in both genotypes. In addition, infusion of PGE2 into WT mice induced bladder overactivity, an effect that was significantly blunted in the EP3 KO mice. The data reported here provide the first evidence supporting a functional role for EP3 receptors in normal urinary bladder function and implicate EP3 as a contributor to bladder overactivity during pathological conditions of enhanced PGE2 production, as reported previously in overactive bladder patients.

scholarly journals Urinary bladder hypertrophy characteristic of male ROMK Bartter’s mice does not occur in female mice

2018 ◽  
Vol 314 (3) ◽  
pp. R334-R341 ◽  
Author(s):  
Jun-Mo Kim ◽  
Shuhua Xu ◽  
Xiaoyun Guo ◽  
Haiyan Hu ◽  
Ke Dong ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Bladder ◽  
Sex Difference ◽  
Bladder Capacity ◽  
Detrusor Muscle ◽  
Mrna Levels ◽  
Wild Type ◽  
Salt Wasting ◽  
Similar Phenotype ◽  
Bladder Weight

The renal outer medullary potassium channel (ROMK; Kir1.1) plays an important role in Na+ and K+ homeostasis. ROMK knockout (KO) mice show a similar phenotype to Bartter’s syndrome of salt wasting and dehydration due to reduced Na-2Cl-K-cotransporter activity but not in ROMK1 KO mice. ROMK KO mice also show hydronephrosis; however, the mechanism of this phenotype has not been understood. We have previously demonstrated a gender-sex difference in hydronephrosis and PGE2 production in ROMK KO mice. In this study we compared the gender-sex difference in bladder hypertrophy and hydronephrosis in ROMK KO mice. The bladder weight, bladder capacity, and the thickness of urothelium in male ROMK KO showed average increased two to approximately fourfold greater than wild-type (WT) mice, but there was no difference in either female or ROMK1 KO mice. The thickness of the urothelium was 648.8 ± 33.2 µm vs. 302.7 ± 16.5 µm ( P < 0.001) and the detrusor muscle 1,940.7 ± 98.9 µm vs. 1,308.2 ± 102.1 µm ( P = 0.013), respectively, in 12-mo male ROMK KO mice compared with the same age WT mice. Western blotting detected ROMK expression at 45~48 kDa, and both ROMK1 and ROMK2 mRNA were detected by quantitative PCR in the bladder. Immunofluorescence staining showed ROMK stained in the bladder, ureter, and urethra in WT but not in KO. In addition, there was a correlation between the severity of hydronephrosis and the bladder weight in male but not in female ROMK KO mice. In conclusion, ROMK expressed in the urinary tract at both protein and mRNA levels; significant enlargement and hypertrophy of the bladder may contribute to hydronephrosis in male ROMK KO mice.

The role of the peripheral cannabinoid system in the pathogenesis of detrusor overactivity evoked by increased intravesical osmolarity in rats

2015 ◽  
Vol 93 (8) ◽  
pp. 721-726 ◽  
Author(s):  
Kajetan Juszczak ◽  
Piotr Maciukiewicz
Keyword(s):  
Urinary Bladder ◽  
Detrusor Overactivity ◽  
Cannabinoid Receptors ◽  
Bladder Capacity ◽  
Pressure Profile ◽  
Intravesical Instillation ◽  
Motility Index ◽  
Urinary Bladder Dysfunction ◽  
Cb2 Receptors ◽  
Cb1 And Cb2 Receptors

The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO). We compared urinary bladder activity in response to blockade of CB1 and CB2 receptors using AM281 and AM630, respectively, in normal rats and after hyperosmolar stimulation. Experiments were performed on 44 rats. DO was induced by intravesical instillation of hyperosmolar saline. Surgical procedures and cystometry were performed under urethane anaesthesia. The measurements represent the average of 5 bladder micturition cycles. We analysed basal, threshold, and micturition voiding pressure; intercontraction interval; compliance; functional bladder capacity; motility index; and detrusor overactivity index. The blockage of CB1 and CB2 receptors diminished the severity of hyperosmolar-induced DO. In comparison with naïve animals the increased frequency of voiding with no significant effect on intravesical voiding pressure profile was observed as a result of the blockage of CB1 and CB2 receptors. These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction.

scholarly journals Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents

2008 ◽  
Vol 295 (5) ◽  
pp. H1905-H1916 ◽  
Author(s):  
Andrianos Kontogeorgis ◽  
Xiaodong Li ◽  
Eunice Y. Kang ◽  
Jonathan E. Feig ◽  
Marc Ponzio ◽  
...  
Keyword(s):  
Gap Junction ◽  
Ventricular Myocytes ◽  
Critical Role ◽  
Mouse Heart ◽  
Wild Type ◽  
Short Term ◽  
Wild Type Littermate ◽  
Cx43 Expression ◽  
Significant Prolongation ◽  
Electrophysiological Effects

Gap junction redistribution and reduced expression, a phenomenon termed gap junction remodeling (GJR), is often seen in diseased hearts and may predispose toward arrhythmias. We have recently shown that short-term pacing in the mouse is associated with changes in connexin43 (Cx43) expression and localization but not with increased inducibility into sustained arrhythmias. We hypothesized that short-term pacing, if imposed on murine hearts with decreased Cx43 abundance, could serve as a model for evaluating the electrophysiological effects of GJR. We paced wild-type (normal Cx43 abundance) and heterozygous Cx43 knockout (Cx43+/−; 66% mean reduction in Cx43) mice for 6 h at 10–15% above their average sinus rate. We investigated the electrophysiological effects of pacing on the whole animal using programmed electrical stimulation and in isolated ventricular myocytes with patch-clamp studies. Cx43+/− myocytes had significantly shorter action potential durations (APD) and increased steady-state ( Iss) and inward rectifier ( IK1) potassium currents compared with those of wild-type littermate cells. In Cx43+/− hearts, pacing resulted in a significant prolongation of ventricular effective refractory period and APD and significant diminution of Iss compared with unpaced Cx43+/− hearts. However, these changes were not seen in paced wild-type mice. These data suggest that Cx43 abundance plays a critical role in regulating currents involved in myocardial repolarization and their response to pacing. Our study may aid in understanding how dyssynchronous activation of diseased, Cx43-deficient myocardial tissue can lead to electrophysiological changes, which may contribute to the worsened prognosis often associated with pacing in the failing heart.

Ameliorating effects of cloperastine on dysfunction of the urinary bladder caused by cerebral infarction in conscious rats

2009 ◽  
Vol 87 (11) ◽  
pp. 893-899 ◽  
Author(s):  
Gen Yamamoto ◽  
Fumio Soeda ◽  
Tetsuya Shirasaki ◽  
Kazuo Takahama
Keyword(s):  
Urinary Bladder ◽  
Cerebral Infarction ◽  
Flow Rate ◽  
Bladder Capacity ◽  
Left Middle Cerebral Artery ◽  
Sprague Dawley ◽  
Urinary Bladder Dysfunction ◽  
Sprague Dawley Rats ◽  
Urethral Resistance ◽  
Effective Doses

We investigated the effects of the centrally acting antitussives dextromethorphan and cloperastine on urinary bladder dysfunction 24 h after cerebral infarction in rats using the cystometry technique. First, cystometrography was performed in conscious male Sprague–Dawley rats. Cerebral infarction was then induced by occlusion of the left middle cerebral artery. Twenty-four hours after cerebral infarction, the effect of each drug on micturition disorder was estimated for 5 parameters: bladder capacity, maximum voiding pressure, micturition latency, flow rate, and urethral resistance. Cerebral infarction markedly reduced bladder capacity, micturition latency, and flow rate and increased urethral resistance. After cerebral infarction, intravenous dosing of saline had no effect on these parameters. Dextromethorphan (20 mg/kg) and cloperastine (2.5 and 5.0 mg/kg) at antitussive effective doses significantly increased bladder capacity and micturition latency. Unlike dextromethorphan, cloperastine ameliorated decreases in flow rate and increases in urethral resistance caused by cerebral infarction. These results suggest that cloperastine may have therapeutic value for the treatment of disorders of the micturition reflex associated with cerebral infarction, and that the drug may become a base compound from which to develop more active drugs for such disorders.

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