Abstract
To measure the relative transcription of adenosine receptor subtypes and the contractile effects of adenosine and selective receptor-subtype ligands on detrusor smooth muscle from patients with neuropathic overactive (NDO) and stable bladders and also from guinea-pigs. Contractile function was measured at 37°C in vitro from detrusor smooth muscle strips. Contractions were elicited by superfusate agonists or by electrical field stimulation. Adenosine-receptor (A1, A2A, A2B, A3) transcription was measured by RT-PCR. Adenosine attenuated nerve-mediated responses with equivalent efficacy in human and guinea-pig tissue (pIC50 3.65–3.86); the action was more effective at low (1–8 Hz) compared to high (20–40 Hz) stimulation frequencies in human NDO and guinea-pig tissue. With guinea-pig detrusor the action of adenosine was mirrored by the A1/A2-agonist N-ethylcarboxamidoadenosine (NECA), partly abolished in turn by the A2B-selectve antagonist alloxazine, as well as the A1-selective agonist N6- cyclopentyladenosine (CPA). With detrusor from stable human bladders the effects of NECA and CPA were much smaller than that of adenosine. Adenosine also attenuated carbachol contractures, but mirrored by NECA (in turn blocked by alloxazine) only in guinea-pig tissue. Adenosine receptor subtype transcription was measured in human detrusor and was similar in both groups, except reduced A2A levels in overactive bladder. Suppression of the carbachol contracture in human detrusor is independent of A-receptor activation, in contrast to an A2B-dependent action with guinea-pig tissue. Adenosine also reduced nerve-mediated contractions, by an A1- dependent action suppressing ATP neurotransmitter action.Electronic supplementary materialThe online version of this article (doi:10.1007/s00210-016-1255-1) contains supplementary material, which is available to authorized users.
Highlights
The purinergic system regulates bladder function through the action of ATP or its metabolites
This study described the contractile effects of adenosine, via these receptor subtypes, in isolated human detrusor from patients with stable bladders and those with neuropathic detrusor overactivity
Atropine-resistant contractions in human NDO (Fig 1a inset, upper panel) and guinea-pig detrusor were abolished by P2X1 receptor desensitisation with 1 μM ABMA - consistent with ATP as a functional neurotransmitter
Summary
The purinergic system regulates bladder function through the action of ATP or its metabolites. ATP and its immediate breakdown product ADP have been extensively studied through their respective actions on purinergic P2X and P2Y receptors. ATP is a functional excitatory neurotransmitter in most animal and human overactive bladders (Bayliss et al 1999; Fry et al, 2011). ADP has a negative inotropic effect on detrusor smooth muscle (McMurray et al, 1998) but activates suburothelial interstitial cells and increases spontaneous bladder contractions (Fry et al 2012). A breakdown product of ATP via endonucleo tidases, is a P1 receptor agonist. It relaxes agonist-induced detrusor contractions (Rubinstein et al 1998) and attenuates stretch-activated urothelial ATP release (Dunning-Davies et al 2013).
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