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Histamine‐induced increases in cyclic AMP levels in bovine adrenal medullary cells
Author(s) -
Marley Philip D.,
Thomson Kerrie A.,
Jachno Kim,
Johnston Matthew J.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12515.x
Subject(s) - dimaprit , histamine , cimetidine , thioperamide , agonist , endocrinology , mepyramine , medicine , histamine h2 receptor , chemistry , metiamide , receptor , antagonist , biology , histamine h3 receptor
1 The effect of histamine on cellular cyclic AMP levels in cultured bovine adrenal medullary cells has been studied. 2 Histamine (0.3–30 μ m ) increased cyclic AMP levels transiently, with a maximal response after 5 min, a smaller response after 20 min, and no increase seen after 80 or 180 min. The EC 50 at 5 min was approximately 2 μ m . Histamine had no effect on cyclic AMP release from the cells over 5 min, but increased it after 90 min. 3 The cyclic AMP response to 5 μ m histamine was reduced by 45% by 1 μ m mepyramine and by almost 30% by 1 μ m cimetidine, and was abolished by the combination of both antagonists. Cimetidine at 100 μ m did not inhibit the response to histamine more than 1 μ m cimetidine. The H 3 ‐receptor antagonist, thioperamide (1 μ m ), had no effect on the response to histamine. 4 The H 1 ‐receptor agonist, 2‐thiazolylethylamine (5–100 μ m ) and the H 2 ‐receptor agonist, dimaprit (5–100 μ m ), each induced a cyclic AMP response, and gave more‐than‐additive responses when combined. The H 3 agonist ( R )α‐methylhistamine (100 μ m ) had no effect either on its own or in combination with either the H 1 or the H 2 agonist. The response to 100 μ m 2‐thiazolylethylamine was unaffected by cimetidine (100 μ m ). 5 The cyclic AMP responses to 5μ m histamine, 100 μ m thiazolylethylamine and 100 μ m dimaprit were each weakly enhanced in the presence of 1 m m 3‐isobutyl‐1‐methylxanthine. The response to dimaprit was enhanced more than 10 fold in the presence of 0.3 μ m forskolin, while the responses to histamine and thiazolylethylamine were weakly enhanced. 6 The cyclic AMP response to 5 μ m histamine was partially reduced in the absence of extracellular Ca 2+ , and the residual response was fully antagonized by 1 μ m cimetidine and was unaffected by 1 μ m mepyramine. In the absence of Ca 2+ , the cyclic AMP response to 100 μ m thiazolylethylamine was abolished, while that to 100 μ m dimaprit was unaffected. 7 Reincubation of 5 μ m histamine solutions with a second set of chromaffin cells, following prior incubation with another set of cells, induced a cyclic AMP response in the fresh cells. This response was reduced by a combination of mepyramine and cimetidine to the same degree as the response to fresh 5 μ m histamine solutions. 8 The results indicate that histamine increases cellular cyclic AMP levels in bovine chromaffin cells by three mechanisms: by acting on H 1 receptors, by acting on H 2 receptors, and by an interaction between H 1 and H 2 receptors. The H 1 response does not require concomitant activation of H 2 receptors, is fully dependent on extracellular Ca 2+ , does not depend on secreted chromaffin cell products, and is not due to reduced cyclic AMP degradation or export. The H 2 cyclic AMP response is the first functional response reported for H 2 receptors on chromaffin cells, is independent of Ca 2+ , is not due to reduced cyclic AMP export or degradation, and is likely to be mediated via a direct action through G s . The role of these different mechanisms in the regulation of cyclic AMP‐dependent processes in chromaffin cells by histamine is under investigation.