Adenosine antagonism and related effects of theophylline derivatives in guinea pig ileum longitudinal muscle.
Alkylxanthines, such as theophylline and 8-(p-sulfo)phenyltheophylline were found to enhance contractile responses to transmural nerve stimulation in guinea pig ileum longitudinal muscle. At higher concentrations, theophylline and the non-sulfonylated compound 8-phenyltheophylline inhibited contractile responses, an action not observed with the sulfoderivative. Direct muscle responses to electrical stimulation in the presence of tetrodotoxin were markedly inhibited by theophylline but were unaltered by 8-(p-sulfo)phenyltheophylline. During nerve stimulation acetylcholine release, as measured by gas chromatography-mass spectrometry, was significantly increased by application of 8-(p-sulfo)phenyltheophylline. The enhancing action by alkylxanthines is thus due to a prejunctional effect, via increased transmitter release. The enhancing action was most marked with the sulfo-derivative, which also showed characteristics of truly competitive adenosine antagonism, with slope of unity in Schild plots, when 2-chloradenosine was used as agonist. The enhancing action by 8-(p-sulfo)phenyltheophylline was unaffected by the cyclic AMP phosphodiesterase inhibitor, ZK 62.711, which, however, enhanced the postjunctional inhibitory action of theophylline. It is thus suggested that alkylxanthine derivatives have a prejunctional enhancing action due to adenosine antagonism, and a postjunctional inhibitory action due to cyclic AMP phosphodiesterase inhibition. Furthermore, 8-(p-sulfo)phenyltheophylline is suggested to be selectively acting on extracellular adenosine receptors, and lacking in phosphodiesterase inhibition, because of negligible intracellular penetration due to its permanent charge in aqueous solution. Purine modulation of neurotransmission is more pronounced in the ileum, than previously understood.
D015762:2-Chloroadenosine; D000109:Acetylcholine / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002794:Choline / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000294:innervation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology*
D011760:Pyrrolidinones; D015762:2-Chloroadenosine; D013779:Tetrodotoxin; D001285:Atropine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D020889:Rolipram; D000241:Adenosine; D002794:Choline; D000109:Acetylcholine