Theophylline interferes with the modulatory role of endogenous adenosine on cholinergic neurotransmission in guinea pig ileum

Abstract

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 .mu.M), 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 and a pure cAMP phosphodiesterase inhibitor, ZK 62, 711 [4-(3-cyclopentyloxy-4-methoxyphenyl)-2-2-pyrrolidone] inhibited contractile responses. Dipyridamole and dilazep, inhibitors of adenosine inactivation and selective inhibitors of cAMP and cGMP phosphodiesterase, respectively, enhanced effects of exogenous adenosine and caused a marked leftward shift of adenosine threshold dose. When dipyridamole 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 [high pressure liquid chromatography]. Due to tissue and microbial adenosine inactivation direct estimates of extracellular adenosine concentration could not be obtained. 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.