SUPPRESSION OF CAMP FORMATION BY ADENOSINE IN MYENTERIC GANGLIA FROM GUINEA-PIG SMALL-INTESTINE

Effects of the adenosine receptor agonist 2-chloro-N-6-cyclopentyl-ade nosine (CCPA) on stimulation of cAMP formation by histamine, 5-hydroxy tryptamine, substance P and forskolin were determined for enzymaticall y dissociated ganglia from the myenteric plexus of guinea-pig small in testine. Each of the 4 substances stimulated cAMP production. CCPA blo cked the stimulation of cAMP by histamine, but not by 5-hydroxytryptam ine or substance P. CCPA marginally suppressed stimulation by forskoli n. CCPA alone suppressed basal levels of cAMP. The adenosine receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) reversed the inhib itory action of CCPA on stimulation of cAMP formation by histamine. Ex posure to adenosine deaminase or CPT increased cAMP in the ganglia. Th e results are consistent with a hypothesis that stimulation of adenyla te cyclase and elevation of intraneuronal cAMP in enteric neurons are steps in the signal transduction cascade for the excitatory actions of 5-hydroxytryptamine, substance P and histamine. They are consistent a lso with an original hypothesis from electrophysiologic studies which states that stimulation of adenosine A, receptors suppresses cAMP form ation and thereby slow synaptic excitation in response to histamine, b ut not to 5-hydroxytryptamine or substance P. The results support evid ence from intracellular microelectrode studies which suggested that en dogenous adenosine accumulates to levels sufficient for tonic suppress ion of cAMP formation in myenteric ganglia in vitro.