1 The characteristics of histamine-stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation in slices of rabbit cerebral cortex have been investigated. 2 The selective H2-receptor antagonists, cimetidine, tiotidine, metiamide and ranitidine appeared to antagonize the stimulation ofcyclic AMP accumulation elicited by histamine in a competitive manner consistent with an interaction with histamine H2-receptors. 3 The H,-receptor antagonist mepyramine (0.8 tM) produced only a weak inhibition of the response to histamine. The inhibition appeared to be non-competitive producing a decrease in the maximal response with little effect on the EC50 value. 4 The specific H2-receptor agonist, impromidine, produced a maximum response of only 31 ± 2% of that obtained with histamine. Studies with histamine and impromidine in combination indicated that impromidine was not acting as a partial agonist. 2-Thiazolylethylamine, a selective HI-agonist, produced only a weak response (EC50 -1 mM) yielding a relative potency with respect to histamine (= 100) of 2.5. 5 In the presence of a supramaximal concentration of impromidine, histamine and 2-thiazolylethylamine further elevated the response to impromidine. In these conditions the relative potency of 2-thiazolylethylamine was increased to 59 (histamine = 100), a value which was comparable with that reported for H1-receptor-mediated contractions of guinea-pig ileum.6 The HI-receptor antagonists mepyramine, promethazine, triprolidine and chlorpheniramine competitively antagonized the potentiation of impromidine-stimulated cyclic AMP accumulation elicited by histamine and 2-thiazolylethylamine in rabbit cerebral cortex without affecting the response to impromidine alone. (+ )-Chlorpheniramine was some 150 fold more potent than the (-)-isomer in this respect. 7 Histamine and adenosine in combination had a much greater than additive effect on the accumulation of cyclic AMP in rabbit cerebral cortical slices. The potentiation of the adenosine response could be partially but not completely antagonized by either cimetidine or mepyramine. 8 In the presence of H2-receptor blockade with 0.02mM tiotidine, histamine elicited a significant potentiation (EC50 44 ;M) of the response to adenosine. This response was antagonized competitively by mepyramine yielding a KB value of 0.0511M similar to that obtained from inhibition of the potentiation of impromidine-stimulated accumulation of cyclic AMP (0.02 AtM). 9 These results suggest that there are two components in the response to histamine in rabbit cerebral cortical slices. The first component appears to be mediated by histamine H2-receptors while the second, mepyramine-sensitive, component has some ofthe characteristics ofan H,-receptor mediated response and requires prior stimulation of adenosine-or H2-receptors to produce its effect.
1The effect of calcium on the H,-and H2-receptor components of the cyclic AMP response to histamine in rabbit cerebral cortical slices has been investigated. 2 Removal of calcium ions from the incubation medium during the preparation, preincubation and final incubation of brain slices significantly reduced the cyclic AMP responses to adenosine, histamine and the H2-selective agonist, impromidine. 3 Removal of calcium ions from the incubation medium during only the final incubation with agonists did not influence the responses to adenosine, histamine, impromidine and the H,-selective agonist, 2-thiazolylethylamine. 4 Final incubation of rabbit cerebral cortical slices in calcium-free buffer containing EGTA (I mM) however, selectively reduced the cyclic AMP responses to the H,-agonists histamine and 2-thiazolylethylamine without affecting the response to impromidine or adenosine. 5 These latter incubation conditions significantly reduced the maximal extent of the augmentation of impromidine-or adenosine-stimulated cyclic AMP accumulation produced by H,-receptor stimulation, without affecting the EC, values of the H,-agonists. Calcium-free/EGTA conditions did not, however, alter the dose-response parameters for the response to the H2-agonist, impromidine. 6 These data provide further evidence that the two histamine receptor systems affect cyclic AMP accumulation in rabbit cerebral cortical slices by different mechanisms.
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