Theophylline interferes with the modulatory role of endogenous adenosine on cholinergic neurotransmission in guinea pig ileum.
The ability of theophylline and other phosphodiesterase inhibitors to alter contractile responses to cholinergic nerve stimulation was investigated in isolated longitudinal muscle of the guinea pig ileum. Theophylline in low concentrations (10-100 microM), having no or little effect on measured phosphodiesterase activity, antagonized inhibitory effects of exogenous adenosine. In higher concentrations (0.1-10 mM), shown to be effective in inhibiting phosphodiesterase, theophylline as well as a "pure" cAMP phosphodiesterase inhibitor, ZK 62, 711, inhibited contractile responses. Dipyridamole and dilazep, inhibitors of adenosine inactivation, and also selective inhibitors of cAMP and cGMP phosphodiesterase, respectively, were found to enhance effects of exogenous adenosine and to cause a marked leftward shift to adenosine threshold dose. When dipyridamole and dilazep by themselves had inhibitory effects these could be antagonized by theophylline, suggesting an action through increased levels of endogenous adenosine. As a further indication of endogenous adenosine modulating neurotransmission low concentrations of theophylline enhanced responses to transmural stimulation. Endogenous purine concentrations in tissues and bath media were measured by HPLC. Because of tissue and microbial adenosine inactivation direct estimates of extracellular adenosine concentration could not be obtained. However, adenosine levels increased during transmural stimulation, and during inhibition of adenosine inactivation were sufficient, even in the bath medium, to interfere with the cholinergic neurotransmission.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D002799:Cholinergic Fibers / Q000187:drug effects*; D003517:Cyclopentanes / Q000494:pharmacology; D004109:Dilazep / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000201:enzymology / Q000294:innervation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009705:Nucleosides / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D009435:Synaptic Transmission / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology*
D003517:Cyclopentanes; D009705:Nucleosides; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D004176:Dipyridamole; D013806:Theophylline; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D004109:Dilazep; D020889:Rolipram