Abstract
As adenosine 5'-triphosphate (ATP) is one of the inhibitory mediators of the bladder outflow region, this study investigates the possible release of ATP or related purines in response to electrical field stimulation (EFS) and the purinoceptor(s) involved in nerve-mediated relaxations of the pig urinary bladder neck. Urothelium-denuded and intact phenylephrine-precontracted strips were mounted in organ baths containing physiological saline solution at 37 degrees C and gassed with 95% O(2) and 5% CO2 for isometric force recordings. EFS, in the presence of atropine, guanethidine and N(G)-nitro-L-arginine, and exogenous purines, produced frequency- and concentration-dependent relaxations respectively. Adenosine 5'-diphosphate (ADP) and adenosine were more potent than ATP in producing relaxation, while uridine 5'-triphosphate, uridine 5'-diphosphate and alpha,beta-methylene ATP were less effective. The non-selective P2 antagonist suramin, and the P2Y(1) and P1 receptor blockers 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate tetrasodium and 8-(p-sulphophenyl)theophylline, respectively, inhibited the responses to EFS and ATP. The P1 agonist's potency was: 5'-N-ethylcarboxamidoadenosine (NECA)>4-2[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzene propanoic acid hydrochloride>2-chloro-N(6)-cyclopentyladenosine>-2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-b-D-ribofuranuronamide = adenosine. 4-(-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl) phenol, an A(2A) antagonist, reduced the relaxations to EFS, adenosine and NECA. In urothelium-intact samples, relaxations to EFS and purines were smaller than in urothelium-denuded preparations. Neuronal voltage-gated Na(+) channels blockade failed to modify ATP relaxations. At basal tension, EFS- and ATP-induced contractions were resistant to desensitization or blockade of P2X(1) and P2X(3) receptors. ATP is involved in the non-adrenergic, non-cholinergic, non-nitrergic inhibitory neurotransmission in the pig bladder neck, producing relaxation largely through muscle A(2A) receptors after breakdown to adenosine, and P2Y(1) receptors after breakdown to ADP. Antagonists of these receptors may be useful for urinary incontinence treatment produced by intrinsic sphincteric deficiency.
Highlights
Background and purposeAs adenosine 5′-triphosphate (ATP) is one of the inhibitory mediators of the bladder outflow region, this study investigates the possible release of ATP or related purines in response to electrical field stimulation (EFS) and the purinoceptor(s) involved in nerve-mediated relaxations of the pig urinary bladder neck
Results are expressed as mean Ϯ SEM of n experiments. *#WP < 0.05 versus ATP, Adenosine 5′-diphosphate (ADP) and UTP respectively. a,b-meATP, a,b-methylene adenosine 5′-triphosphate; ADP, adenosine 5′-diphosphate; ATP, adenosine 5′-triphosphate; pEC20 = -log EC20, where EC20 is the concentration of agonist producing 20% relaxation of phenylephrine (PhE)-induced contraction; R is the relaxation, expressed as a percentage of the PhE-induced contraction, evoked at the highest concentration of agonist used: ATP, 1 mM; ADP, 1 mM; UTP, 1 mM; UDP, 1 mM; and a,b-meATP, 300 mM; UDP, uridine 5′-diphosphate; UTP, uridine 5′-triphosphate
Results are expressed as mean Ϯ SEM of n experiments. *P < 0.05 versus control. 8-SPT, 8-(p-sulphophenyl)theophylline; ADP, adenosine 5′-diphosphate; ATP, adenosine 5′-triphosphate; MRS2179, 2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate tetrasodium; MRS2211, 2-[(2-chloro-5-nitrophenyl)azo]5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridine carboxaldehyde; pEC50 = -log EC50, where EC50 is the concentration of agonist producing 50% relaxation of phenylephrine (PhE)-induced contraction; PPADS, pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid); R is the relaxation, expressed as a percentage of the PhE-induced contraction, evoked at the highest concentration of agonist used: ATP, 1 mM; and ADP, 1 mM
Summary
As adenosine 5′-triphosphate (ATP) is one of the inhibitory mediators of the bladder outflow region, this study investigates the possible release of ATP or related purines in response to electrical field stimulation (EFS) and the purinoceptor(s) involved in nerve-mediated relaxations of the pig urinary bladder neck. Conclusions and implications: ATP is involved in the non-adrenergic, non-cholinergic, non-nitrergic inhibitory neurotransmission in the pig bladder neck, producing relaxation largely through muscle A2A receptors after breakdown to adenosine, and P2Y1 receptors after breakdown to ADP. Antagonists of these receptors may be useful for urinary incontinence treatment produced by intrinsic sphincteric deficiency. British Journal of Pharmacology (2009) 157, 1463–1473; doi:10.1111/j.1476-5381.2009.00314.x; published online 25 June 2009
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