Is histamine potentiation of adenosine-stimulated cyclic AMP accumulation in guinea-pig cerebral cortical slices mediated by products of inositol phospholipid breakdown?

In several brain tissues the accumulation of cyclic AMP induced by directly acting stimulants, such as isoprenaline, adenosine or histamine (Hr) can be potentiated by histamine HI-receptor agonists [l-3]. The potentiation of adenosine-coupled cyclic AMP accumulation has proved useful in quantitative studies of functional H,-receptors in guinea-pig cerebral cortical slices [4, 51, but the recent demonstration that adenosine deaminase and histidine decarboxylase may be present in the same nerve fibres in rat brain [6] has given studies of the nature of the adenosinehistamine Hi-agonist interaction a particular functional relevance. The mechanism of the potentiating effect of histamine has been generally assumed to be mediated by a rise in free intracellular Ca2+ and there is some experimental support for this proposition [7]. However, evidence has been presented recently that in S49 lymphoma cells [8] and in rat pinealocytes [9] the accumulation of cyclic AMP induced by isoprenaline can be stimulated by a phorbol ester, PMA (phorbol 12-myristate-13-acetate), an activator of protein kinase C [lo, 111. The activation of protein kinase C would normally be expected to be the result of agonist-induced inositol phospholipid breakdown, with the consequent formation of 1,2-diacylglycerol[12]. Of particular interest with respect to the mechanism of the HI-agonist potentiation is the report [13] that 2-chloroadenosine-elicited accumulation of cyclic AMP in particulate preparations from guinea-pig cerebral cortex is enhanced by PMA. However, very much higher concentrations of PMA (>2@f) were required than those normally necessary for protein kinase C activation (l-10 nM) [ll]. We have set out to examine the effect of PMA on the response to adenosine in slices of guinea-pig cerebral cortex and to determine whether a stimulation of cyclic AMP accumulation can be obtained at lower concentrations of PMA if activation of the other arm of the inositol phospholipid pathway, Ca*+ release induced by inositol1,4,5trisphosphate, is mimicked by the presence of small concentrations of the calcium ionophore A23187.