Characterization of histamine receptors mediating the stimulation of cyclic AMP accumulation in rabbit cerebral cortical slices

Abstract

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.

The role of calcium in the cyclic AMP response to histamine in rabbit cerebral cortical slices

“…This was achieved in the present study when slices of rabbit cerebral cortex were prepared and incubated in calcium-containing medium before incubation with agonists in calciumfree medium containing 1 mM EGTA (see for example Figure 5). Under these less severe calcium-depleting conditions the responses to histamine and 2-TEA, which have a marked H,-component (Al-Gadi & Hill, 1985), were substantially reduced while the responses to adenosine and the H2-selective agonist impromidine were not significantly affected. A more direct evaluation of the effect of calcium on the H,-receptor response was made by investigating the augmentation produced by H,-agonists of the cyclic AMP response to a fixed concentration of impromidine or adenosine.…”

“…It should be noted that a response to the HI-agonist 2-TEA alone was obtained (Figure 4) because of its effect on H2-receptors at high (i.e. 1 mM) concentrations (Al-Gadi & Hill, 1985). Under these conditions the cyclic AMP response to 2-TEA, like that to histamine, has two components: a direct H2-effect and a marked H,-effect which acts to amplify the H2- .…”

“…The fact that these two effects occur at free calcium concentrations thought to exist intracellularly (Piascik et al, 1980) is therefore consistent with our finding that the responses to impromidine and adenosine in rabbit cerebral cortical slices are inhibited when the calcium content is depleted by 80%. Under these conditions the various non-ionic pools of calcium in the plasma membrane, endoplasmic reticulum and mitochondria (Rasmussen & Barret, 1984) (Al-Gadi & Hill, 1985) means that the observed loss of responsiveness to histamine under severe calcium depleting conditions (e.g. Figures 1 and 2) cannot be taken as evidence that the H,-response is also calcium-dependent.…”

“…Histamine produces a large accumulation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in guinea-pig (Daly, 1977;Hill et al, 1981;Daum et al, 1982) and rabbit (Kakiuchi & Rall, 1968;Al-Gadi & Hill, 1985) brain slices. This response to histamine can be mediated by both H.-and H2-receptor subtypes (Daly, 1977;Palacios et al, 1978;Hill et al, 1981;AlGadi & Hill, 1985).…”

“…adenosine A2) which is linked directly to the cyclic AMP synthesizing enzyme, adenylate cyclase (AlGadi produces a large augmentation of the cyclic AMP response to the selective H2-agonist impromidine, or of that produced by adenosine, but is without effect on the cyclic AMP generating system on its own (Al-Gadi & Hill, 1985). A similar H,-mediated augmentation of the response to H2-agonists, adenosine or vasoactive intestinal polypeptide (VIP) has also been reported in slices of mouse cerebral cortex (Magistretti & Schorderet, 1985), guinea-pig hippocampus (Palacios et al, 1978) and guinea-pig cerebral cortex (Hill et al, 1981;Daum et al, 1982;.…”