Cyclic Adenosine 3′,5′-Monophosphate in Guinea Pig Cerebral Cortical Slices: II. THE ROLE OF PHOSPHODIESTERASE ACTIVITY IN THE REGULATION OF LEVELS OF CYCLIC ADENOSINE 3′,5′-MONOPHOSPHATE

Abstract

Abstract Elevated levels of cyclic adenosine 3',5'-monophosphate (cyclic AMP) in guinea pig cerebral cortical slices after incubations with histamine, histamine-norepinephrine, adenosine, and combinations of adenosine and biogenic amines rapidly return to basal levels (t½ l 10 min) during subsequent incubations in control medium. Elevated intracellular levels return only slowly to basal levels after stimulation with the depolarizing agent, veratridine. The rate of apparent degradation of cyclic AMP may be somewhat limited by the rate of diffusion of stimulatory test agents out of the brain slices. The time courses for the diappearance of total cyclic AMP and of radioactive cyclic AMP, the latter derived from intracellular radioactive nucleotides labeled by a prior incubation with radioactive adenine, follow similar patterns. The phosphodiesterase inhibitors, papaverine and isobutylmethylxanthine, potentiate the accumulation both of total and of radioactive cyclic AMP elicited by histamine or by histamine-norepinephrine and in addition decrease the rate of degradation of cyclic AMP after removal of the stimulatory agents. Isobutylmethylxanthine potentiates the histamine-elicited accumulation of total cyclic AMP to a greater extent than the accumulation of radioactive cyclic AMP. The potentiative effects of papaverine and isobutylmethylxanthine on accumulations of cyclic AMP are not additive. Papaverine and isobutylmethylxanthine have either no effect or antagonize the accumulations of cyclic AMP evoked by adenosine, adenosine-biogenic amine combinations, or veratridine-histamine, and in addition they do not retard degradation of total and of radioactive cyclic AMP after a prior stimulation by adenosine-histamine-norepinephrine. N,O-Dibutyryl cyclic AMP potentiates the accumulation of radioactive cyclic AMP elicited by histamine or histamine-norepinephrine. The effects of adenosine on cyclic AMP levels are blocked by theophylline and nonpolar analogs, and to a lesser extent by a polar analog, 7-(2'-diethylmethyl-ammoniumethyl)theophylline iodide. Theophylline either has no effect or inhibits the accumulation of cyclic AMP elicited by biogenic amines.