Voltage-gated Na+ Channel Blockers Reduce Functional Bladder Capacity in the Conscious Spontaneously Hypertensive Rat

Clouse, Angela K.; Jugus, M; Eisennagel, Stephen; Laping, Nicholas J.; Westfall, Timothy D.; Thorneloe, Kevin S.

doi:10.1016/j.urology.2012.02.016

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…It is known that Lamotrigine can block Na + channels, but inhibition of Na + channels requires much higher concentrations [ 29 ] than those used in experiments described here. Furthermore, Lamotrigine is devoid of any effect on bladder contractility at higher concentrations required to block Na + channels [ 30 ]. The effect of HCN channels on Ca 2+ influx in detrusor smooth muscles needs to be studied in detail in order to understand the underlying mechanisms for these observations.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the role of HCN channels in β3-adrenoceptor mediated rat bladder relaxation

Kashyap

Yoshimura

Smith

et al. 2015

Bladder

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ObjectiveThe second messenger cAMP is involved in both β3 adrenoceptor (β3-AR) mediated detrusor relaxation and the kinetics of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Here we characterized the effect HCN channel activation and possible interaction with β3-AR in bladder.Materials and MethodsBladder tissues from Sprague-Dawley rats and Human organ donors were obtained for studying species-specific expression of HCN channels by real-time qPCR and Western Blot. Effect of β3-agonist on rat bladder strips (0.5 × 0.5 × 7 mm in size) was studied during activation and blockade of HCN channels by Lamotrigine and ZD7288, respectively.ResultsExpression of all four genes encoding for HCN channels (HCN1-4) was detected separately in bladder mucosa and detrusor from human and rat bladders. Species based differences were evident from relatively higher expression of HCN4 isoform in human bladder and that of HCN1 in rat bladder. Western blot confirmed the findings at mRNA level. Cumulative application β3-AR agonist CL316,243 produced a concentration dependent decrease in resting tension of rat bladder strips expressed as integral of mechanical activity. Pre-incubation of HCN channel blocker ZD 7288 opposed the relaxant effect of CL316,243, whereas co-administration of lamotrigine with CL316,243 at equal molar concentrations caused an additive decrease in resting tension. Cumulative addition of ZD7288 and lamotrigine in absence of CL316,243 showed opposing effects on detrusor contractility.ConclusionsSpecies-specific differences were noted in expression of HCN channels in bladder. Opposing effects ZD7288 and Lamotrigine in the action of β3-AR agonist demonstrate possible functional interaction of HCN channels and β3-AR in detrusor contractility.

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Section: Discussionmentioning

confidence: 99%

Characterization of the role of HCN channels in β3-adrenoceptor mediated rat bladder relaxation

Kashyap

Yoshimura

Smith

et al. 2015

Bladder

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“…The following TRP channel ligands were used: TRPV1, capsaicin; TRPA1, thymol; TRPC3 and TRPC6, carbachol; and TRPM8, icilin (33). Pharmacokinetics were determined as described (10).…”

Section: Methodsmentioning

confidence: 99%

TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

Balakrishna

Song

Achanta

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Jordt S. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 307: L158 -L172, 2014. First published May 16, 2014; doi:10.1152/ajplung.00065.2014.-The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function. acute lung injury; chlorine; TRPV4 ACUTE LUNG INJURY (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), are associated with high levels of morbidity and mortality (28, 37). Major triggers of ALI and ARDS are pneumonia, sepsis, trauma, acid aspiration, inhalation of toxic gases or smoke, hyperoxia, high pressure ventilation, heart failure, or pancreatitis. A major hallmark of ALI and ARDS is the acute increase in permeability of the pulmonary vascular and epithelial barriers, resulting in edema and severe hypoxia (9). ALI and ARDS are often associated with exaggerated inflammatory responses due to neutrophil infiltration and increased macrophage activity in the injured lung (14,22). These inflammatory cells may aggravate injury through protease production, through generation of oxidative reactive species and proinflammatory cytokines and chemokines, and through prevention of inflammation resolution.The ion channel transient receptor potential vanilloid 4 (TRPV4) was recently identified as a major mediator of pulmonary dysfunction in animal models of ventilator-and heart failure-induced ALI, conditions associated with dramatic increases in pulmonary and vascular pressure (17,33). Among other ...

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“…Previous studies reported increased afferent sensitivity in SHRs that may contribute to their bladder hyperactivity [ 15 ]. SHRs show increased voiding frequency, and conversely, decreased BC and MV compared to Wistar rats [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Does Methylphenidate Affect Cystometric Parameters in Spontaneously Hypertensive Rats?

Kim¹,

Jung²,

Choi³

et al. 2015

Int Neurourol J

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Purpose:Methylphenidate (MPH) is one of the most commonly prescribed psychostimulants for attention deficit hyperactivity disorder (ADHD). However, there is limited research on its effects on lower urinary tract function. This study investigated changes in cystometric parameters after intragastric administration of MPH in conscious spontaneously hypertensive rats (SHRs), an animal model of ADHD.Methods:Fourteen- to 16-week-old male SHRs (n=10), weighing between 280 and 315 g, were used. Three micturition cycles were recorded before administering MPH. One hour after each intragastric MPH injection, three cycles of cystometrogram were obtained in the awake condition. Various cystometric parameters were evaluated, including basal pressure (BP), maximal pressure (MP), threshold pressure (TP), bladder capacity (BC), micturition volume (MV), micturition interval (MI), and residual volume (RV). The data were analyzed using paired Student t-tests.Results:Five SHRs were each administered a dose of 3-mg/kg MPH, and the other five received a dose of 6-mg/kg MPH. BP and MP increased significantly in the rats that received the 3-mg/kg MPH injection, but not in those that received the 6-mg/kg injection. BC, MV, and MI significantly increased in the rats that received the 6-mg/kg MPH injection, but not in those that received the 3-mg/kg injection. There were no significant changes in TP after either injection.Conclusions:Significant increases in BC, MV, and MI after the 6-mg/kg MPH injection suggest that the peripheral and the central nervous systems may play important roles in bladder function in those receiving MPH for ADHD.

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Voltage-gated Na+ Channel Blockers Reduce Functional Bladder Capacity in the Conscious Spontaneously Hypertensive Rat

Cited by 5 publications

References 15 publications

Characterization of the role of HCN channels in β3-adrenoceptor mediated rat bladder relaxation

Characterization of the role of HCN channels in β3-adrenoceptor mediated rat bladder relaxation

TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

Does Methylphenidate Affect Cystometric Parameters in Spontaneously Hypertensive Rats?

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