Histamine-sensitive adenylate cyclase in mammalian brain

1 2-Chloroadenosine stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation and potentiated (guinea-pig) or inhibited (mouse) the histamine H1-receptor-stimulated hydrolysis of inositol phospholipids in slices of guinea-pig and mouse cerebral cortex. 2 Two xanthine-based adenosine receptor antagonists were identified which were one order of magnitude more potent at the adenosine receptor mediating augmentation of the histaminestimulated inositol phospholipid hydrolysis than at the receptor linked to cyclic AMP formation in guinea-pig cerebral cortical slices.3 These compounds, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 7-benzyl-3-(2-methylpropyl)xanthine (BMPX) retained their selectivity under near-identical incubation conditions in both assays. 4 These compounds also showed similar affinities and selectivity for the adenosine receptor mediating inhibition of histamine-stimulated inositol phospholipid hydrolysis in mouse cerebral cortical slices.5 Inclusion of agents which give rise to, or mimic, high levels of cyclic AMP (forskolin (1 gM), 8-bromo-cyclic AMP (1 mM) and vasoactive intestinal polypeptide (1 pM)) in the incubation medium failed to mimic the action of 2-chloroadenosine on inositol phospholipid turnover in cerebral cortical slices from either species. 6 These data suggest that the adenosine receptor modulating the hydrolysis of inositol phospholipid in mouse and guinea-pig cerebral cortical slices is different from the adenosine receptor linked to cyclic AMP formation, and, furthermore, that the modulation of inositol phospholipid metabolism in either species is not mediated via alterations in cyclic AMP levels.

Section: Discussionmentioning

confidence: 99%

Section: Accumulation Of 3h-labelled Inositol Phosphatesmentioning

confidence: 99%

Differences in the adenosine receptors modulating inositol phosphates and cyclic AMP accumulation in mammalian cerebral cortex

Alexander

Kendall

Hill

1989

“…In cell-free preparations from guinea-pig cerebral cortex and hippocampus, 'Author for correspondence several workers have demonstrated the presence of a histamine-sensitive adenylate cyclase (Hegstrand et al, 1976;Green et al, 1977;Green, 1983) which appears to be linked exclusively to histamine H2-receptors. In contrast, in slices of guinea-pig cerebral cortex and hippocampus, the effect of histamine on cyclic AMP accumulation appears also to be mediated by histamine H1-receptors.…”

Section: Introductionmentioning

confidence: 99%

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

Al-Gadi

Hill

1985

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 method used was that described by Hegstrand et al (1976). In the experiments with agonist drugs, 50 pl of homogenate, containing approximately 125 pg of protein, was incubated in Tris buffer 50 mM, pH 7.8, containing EGTA 0.6 mM, isobutylmethyl xanthine (IMBX) 1 mM, MgCl2 2 mM, GTP 0.1 mM and various concentrations ofagonist between 10 nM and 10 mm in a total volume of 500 p1.…”

Section: Adenylate Cyclase Assaymentioning

confidence: 99%

A study of the H₂‐receptor for histamine stimulating adenylate cyclase in homogenates of guinea‐pig lung parenchyma

Foreman

Norris²,

Rising³

et al. 1986

1 The effect of forskolin and several H2-agonists was investigated on the activity of adenylate cyclase in homogenates of guinea-pig lung parenchyma. 2 Histamine, 0.I1uM to mM, dimaprit, 1 pM to 10 mm, 4-methyl histamine, 0.1I1M to 10 mM, impromidine, lOnM to 101iM and forskolin, 1 nm to 100 jM, all produced a dose-dependent stimulation of adenylate cyclase activity above the basal level.3 The histamine Hi-receptor antagonist mepyramine, 10 gM, and P-adrenoceptor antagonist propranolol, 10 JM, had no effect on the stimulation by histamine of adenylate cyclase. 4 The dose-response curve for stimulation by histamine of adenylate cyclase was shifted to the right in a dose-dependent manner by increasing concentrations of several H2-antagonists. Schild plots constructed for each H2-antagonist produced straight lines with slopes not significantly different from unity. The equilibrium dissociation constants obtained for the H2-antagonists in this study were similar to those previously reported for inhibition of dimaprit-induced relaxation of the pre-contracted lung strip, inhibition of [3H]-tiotidine binding to homogenates of guinea-pig lung parenchyma and inhibition of histamine-stimulated adenylate cyclase in guinea-pig gastric mucosa.