Prejunctional autoinhibition of purinergic transmission in circular muscle of guinea-pig ileum; a mechanism distinct from P1-purinoceptor activation.
The role of prejunctional purinoceptors (P1-subtype) in the control of ATP-release from inhibitory motoneurons was investigated electrophysiologically, by studying fast purinergic inhibitory junction potentials (IJPs) in guinea-pig ileal circular muscle. Pressure ejections of adenosine and ATP (but not of alpha,beta-methylene ATP) onto circular muscle depressed the amplitude of fast IJPs, indicating the presence of prejunctional P1-purinoceptors. An adenosine (A1/2)-receptor antagonist, theophylline (10(-8)-10(-4) M), increased the amplitude of fast IJPs in a dose-related manner (EC50 = 17.5 microM), suggesting the existence of a basal 'adenosine tone' that regulated ATP-release from ileal motoneurons. However, three methylxanthine derivatives, caffeine (10(-8)-10(-4) M), 3-isobutyl-1-methylxanthine (IBMX; 10(-8)-10(-4) M) and the potent A1-receptor antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (DPCPX; 10(-8)-10(-4) M), failed to potentiate fast IJPs and placed in doubt the existence of this inhibitory adenosine tone. Caffeine and IBMX, but not DCPCX, hyperpolarised ileal circular muscle in a dose-related manner and reduced IJP-amplitude; DPCPX did not alter the amplitude of IJPs. The non-specific inhibitor of phosphodiesterases, Ro-20-1724 (5 x 10(-7)-5 x 10(-5) M), increased the amplitude of fast IJPs, mimicking the actions of theophylline. To this extent, facilitation of inhibitory transmission appeared to involve phosphodiesterase inhibition and modification of intra-axonal cAMP levels and phosphorylation of intra-axonal protein kinases. The phenomenon of IJP rundown, presumed to be a manifestation of prejunctional autoinhibition, was studied using theophylline and DPCPX as A1-receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
King
B F
BF
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism*; D007365:Intercellular Junctions / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D009433:Neural Inhibition; D058914:Purinergic Antagonists; D011687:Purines / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D009435:Synaptic Transmission; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D058914:Purinergic Antagonists; D011687:Purines; D011983:Receptors, Purinergic; D014970:Xanthines; D000255:Adenosine Triphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine