Role of ATP and related purines in inhibitory neurotransmission to the pig urinary bladder neck.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hernández
Medardo
M
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Knight
Gillian E
GE
Wildman
Scott S P
SS
Burnstock
Geoffrey
G
D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D011685:Purine Nucleotides / Q000494:pharmacology / Q000502:physiology*; D058913:Purinergic Agonists; D013552:Swine; D009435:Synaptic Transmission / Q000502:physiology*; D001743:Urinary Bladder / Q000294:innervation / Q000502:physiology*
D011685:Purine Nucleotides; D058913:Purinergic Agonists; D000255:Adenosine Triphosphate