Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder

Silva-Ramos, Miguel; Silva, I.; Faria, Miguel; Magalhães-Cardoso, M.T.; Correia, Joana; Ferreirinha, Fátima; Correia-de-Sá, Paulo

doi:10.1007/s11302-015-9478-z

Cited by 20 publications

(37 citation statements)

References 51 publications

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“…Alternatively, rather than a temporal change in ATP release with duration of diabetes, it may be that ATP metabolism is affected. While to our knowledge there have been no reports of altered ecto‐ATPase activity within the bladder in diabetes, activity of these enzymes is altered in bladder tissues from patients with overactive bladder . Regardless of the underlying mechanism, here we demonstrate temporal changes in intraluminal ATP in diabetic bladder dysfunction, which has not been previously reported.…”

Section: Discussionsupporting

confidence: 48%

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

Lee

Rose’Meyer

McDermott

et al. 2018

Clin Exp Pharma Physio

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Up to 80% of patients with diabetes mellitus develop lower urinary tract complications, most commonly diabetic bladder dysfunction (DBD). The aim of this study was to investigate the impact of diabetes on the function of the inner bladder lining (urothelium). Bladder compliance and intraluminal release of urothelial mediators, adenosine triphosphate (ATP) and acetylcholine (ACh) in response to distension were investigated in whole bladders isolated from 2- and 12-week streptozotocin (STZ)-diabetic rats. Intact and urothelium-denuded bladder strips were used to assess the influence of the urothelium on bladder contractility. Intraluminal ATP release was significantly enhanced at 2 weeks of diabetes, although not at 12 weeks. In contrast, intraluminal ACh release was unaltered by diabetes. Bladder compliance was also significantly enhanced at both 2 and 12 weeks of diabetes, with greatly reduced intravesical pressures in response to distension. Nerve-evoked contractions of bladder strips were significantly greater at 2 weeks of diabetes. When the urothelium was absent, nerve-evoked contractions were reduced, but contractions remained significantly elevated at lower frequencies of stimulation (<5 Hz) in diabetics. Interestingly, although relaxations of bladder strips to isoprenaline were unaltered by diabetes, removal of the urothelium unmasked significantly enhanced relaxations in strips from 2- and 12-week diabetic animals. In conclusion, diabetes alters urothelial function. Enhanced urothelial ATP release may be involved in the hypercontractility observed at early time points of diabetes. These alterations are time-dependent and may contribute to the mechanisms at play during the development of diabetic bladder dysfunction.

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Section: Discussionsupporting

confidence: 48%

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

Lee

Rose’Meyer

McDermott

et al. 2018

Clin Exp Pharma Physio

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“…release through the activation of prejunctional A 1 receptors on bladder cholinergic nerves (Silva et al, 2017;Silva-Ramos et al, 2015) was confirmed further in the present study. Figure 3 shows that transmitter release inhibition caused by mirabegron (0.1 μM, Figure 3b), isoprenaline (1 μM, Figure 3c), and FSK (3 μM, Figure 3d 1 μM), isoprenaline (1 μM), and forskolin (3 μM) were applied 6 min before S 2 either in the absence or in the presence of selective inhibitors of PKA (H-89, 10 μM), EPAC (ESI-09, 10 μM), and ENT1 (Dipy, 0.5 μM), as well as of the adenosine A 1 receptor antagonist, DPCPX (0.1 μM).…”

Section: The Involvement Of Adenosine Release Via Ent1 Transporters Isupporting

confidence: 86%

β₃ Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

Silva

Magalhães-Cardoso

Ferreirinha

et al. 2020

British J Pharmacology

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Background and Purpose The mechanism by which β3 receptor agonists (e.g. mirabegron) control bladder overactivity may involve adenosine release from human and rat detrusor smooth muscle. Retrograde activation of adenosine A1 receptors reduces ACh release from cholinergic bladder nerves. β3‐Adrenoceptors usually couple to adenylyl cyclase. Here we investigated, which of the cAMP targets, protein kinase A or the exchange protein directly activated by cAMP (EPAC) could be involved in this cholinergic inhibition of the bladder. Experimental Approach [3H]ACh and adenosine release from urothelium‐denuded detrusor strips of cadaveric human organ donors and rats were measured by liquid scintillation spectrometry and HPLC, respectively. In vivo cystometry was also performed in urethane‐anaesthetized rats. Key Results The exchange protein directly activated by cAMP (EPAC) inhibitor, ESI‐09, prevented mirabegron‐ and isoprenaline‐induced adenosine release from human and rat detrusor strips respectively. ESI‐09, but not the PKA inhibitor, H‐89, attenuated inhibition of [3H]ACh release from stimulated (10 Hz) detrusor strips caused by activating β3‐adrenoceptors, AC (forskolin) and EPAC1 (8‐CTP‐2Me‐cAMP). Isoprenaline‐induced inhibition of [3H]ACh release was also prevented by inhibitors of PKC (chelerythrine and Go6976) and of the equilibrative nucleoside transporter 1 (ENT1; dipyridamole and NBTI), but not by PLC inhibition with U73122. Pretreatment with ESI‐09, but not with H‐89, prevented the reduction of the voiding frequency caused by isoprenaline and forskolin in vivo. Conclusion and Implications Data suggest that β3‐adrenoceptor‐induced inhibition of cholinergic neurotransmission in human and rat urinary bladders involves activation of an EPAC1/PKC pathway downstream cAMP production resulting in adenosine outflow via ENT1.

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“…Indirect evidence suggests that ATP is released at lower stimulation rates, compared to those releasing ACh (Calvert et al, ; Chakrabarty et al, ; Pakzad et al, ). There is more direct evidence that the PDE‐5 inhibitor sildenafil abolishes nerve‐mediated ATP release (Chakrabarty et al, ); however, this should be set against the observation that ACh is also modulated by agents such as adenosine (Silva‐Ramos et al, ). The development of amperometric ATP‐selective electrodes potentially allows for the real‐time measurement of nerve‐mediated ATP release in detrusor muscle.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications

McCarthy

Ikeda

Skennerton

et al. 2019

British J Pharmacology

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Background and Purpose:This study aims to characterise the molecular mechanisms that determine variability of atropine resistance of nerve-mediated contractions in human and guinea pig detrusor smooth muscle. Experimental Approach: Atropine resistance of nerve-mediated contractions and the role of P2X1 receptors, were assessed in isolated preparations from guinea pigs and also humans with or without overactive bladder syndrome, from which the mucosa was removed. Nerve-mediated ATP release was measured directly with amperometric ATP-sensitive electrodes. Ecto-ATPase activity of guinea pig and human detrusor samples was measured in vitro by measuring the concentrationdependent rate of ATP breakdown. The transcription of ecto-ATPase subtypes in human samples was measured by qPCR. Key Results: Atropine resistance was greatest in guinea pig detrusor, absent in human tissue from normally functioning bladders, and intermediate in human overactive bladder. Greater atropine resistance correlated with reduction of contractions by the ATP-diphosphohydrolase apyrase, directly implicating ATP in their generation. E-NTPDase-1 was the most abundantly transcribed ecto-ATPase of those tested, and transcription was reduced in tissue from human overactive, compared to normal, bladders. E-NTPDase-1 enzymic activity was inversely related to the magnitude of atropine resistance. Nerve-mediated ATP release was continually measured and varied with stimulation frequency over the range of 1-16 Hz. Conclusion and Implications:Atropine resistance in nerve-mediated detrusor contractions is due to ATP release and its magnitude is inversely related to E-NTPDase-1 activity. ATP is released under different stimulation conditions compared with ACh, implying different routes for their release.

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Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder

Cited by 20 publications

References 51 publications

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

β₃ Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications

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Impairment of ATP hydrolysis decreases adenosine A1 receptor tonus favoring cholinergic nerve hyperactivity in the obstructed human urinary bladder

Cited by 20 publications

References 51 publications

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

β3 Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications

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β₃ Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release