Changes in hyperpolarization-activated cyclic nucleotide-gated channel expression and activity in bladder interstitial cells of Cajal from rats with detrusor overactivity

Deng, Tianxing; Zhang, Qian; Wang, Qingqing; Zhong, Xiao; Li, Longkun

doi:10.1007/s00192-015-2632-x

Cited by 20 publications

(21 citation statements)

References 27 publications

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“…The effect of ZD7288 on the concentrations tested here agree with previously reported results [ 12 ] as well with the reported IC50 of ZD7288 for HCN channels, which is in the range of 0.2 μM for heart [ 20 ] and1.8 μM for brain neurons [ 21 ]. There is a risk that higher concentration of ZD7288 (50 μM) used in recent bladder strip studies [ 13 , 22 ] may receive confounding contribution from inhibition of other channels as ZD7288 can block T-type Ca 2+ channels with an IC50 of 100 μM [ 23 ]. ZD7288 at lower dose levels, which are closer to the reported IC50 of ZD7288 for HCN channels, increases the amplitude and frequency of spontaneous contractions.…”

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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“…HCN channels were thought to be the key modulators of bladder ICC-LCs with respect to the conduction of bladder pacemaker activity. 12 In addition, HCN channel expression and function were significantly altered in the bladder ICC-LCs of diabetic cystopathy and detrusor overactive (DO) bladders with partial bladder outlet obstruction (PBOO), 21 , 22 suggesting that HCN channels in bladder ICC-LCs are involved in regulating bladder function in physiological and pathological conditions. To our knowledge, the role of HCN channels in bladder ICC-LCs in cystitis remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Cyclophosphamide-induced HCN1 channel upregulation in interstitial Cajal-like cells leads to bladder hyperactivity in mice

et al. 2017

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are confirmed to be expressed in bladder interstitial Cajal-like cells (ICC-LCs), but little is known about their possible role in cystitis-associated bladder dysfunction. The present study aimed to determine the functional role of HCN channels in regulating bladder function under inflammatory conditions. Sixty female wild-type C57BL/6J mice and sixty female HCN1-knockout mice were randomly assigned to experimental and control groups, respectively. Cyclophosphamide (CYP)-induced cystitis models were successfully established in these mice. CYP treatment significantly enhanced HCN channel protein expression and Ih density and significantly altered bladder HCN1 channel regulatory proteins. Carbachol (CCH) and forskolin (FSK) exerted significant effects on bladder ICC-LC [Ca2+]i in CYP-treated wild-type (WT) mice, and HCN1 channel ablation significantly decreased the effects of CCH and FSK on bladder ICC-LC [Ca2+]i in both naive and CYP-treated mice. CYP treatment significantly potentiated the spontaneous contractions and CCH (0.001–10 μM)-induced phasic contractions of detrusor strips, and HCN1 channel deletion significantly abated such effects. Finally, we demonstrated that the development of CYP-induced bladder overactivity was reversed in HCN1−/− mice. Taken together, our results suggest that CYP-induced enhancements of HCN1 channel expression and function in bladder ICC-LCs are essential for cystitis-associated bladder hyperactivity development, indicating that the HCN1 channel may be a novel therapeutic target for managing bladder hyperactivity.

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“…21 In bladder overactivity, developed in a rat model following partial bladder outlet obstruction, it was shown that the physiological functioning of ICCs changes and the expression of the HCN channels in bladder ICCs significantly increases. [22][23][24] These findings suggest that the HCN channels and ICCs might play an important role in the pathogenesis of detrusor overactivity. Thus, the involvement of the HCN channels is another possible mechanism mediating the inhibition of cholinergic agonist-induced bladder contraction by ivabradine.…”

Section: Discussionmentioning

confidence: 85%

Ivabradine inhibits carbachol-induced contractions of isolated rat urinary bladder

et al. 2018

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Changes in hyperpolarization-activated cyclic nucleotide-gated channel expression and activity in bladder interstitial cells of Cajal from rats with detrusor overactivity

Abstract: All HCN channel isoforms were highly expressed in bladders from the DO group, which was correlated with increased Ih currents in DO ICCs, suggesting that the HCN channels might play an important role in the pathological processes of DO.

Cited by 20 publications

References 27 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

Cyclophosphamide-induced HCN1 channel upregulation in interstitial Cajal-like cells leads to bladder hyperactivity in mice

Ivabradine inhibits carbachol-induced contractions of isolated rat urinary bladder

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