CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FORMATION IN GUINEA‐PIG BRAIN SLICES: EFFECT OF H1‐ AND H2‐HISTAMINERGIC AGONISTS
CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FORMATION IN GUINEA‐PIG BRAIN SLICES: EFFECT OF H1‐ AND H2‐HISTAMINERGIC AGONISTS
复制标题
豚鼠脑切片中环状腺苷 3′,5′-单磷酸盐的形成：H1 和 H2 组胺能激动剂的作用
作者：
K. Dismukes;M. Rogers;J. Daly
- 多种组胺类似物在预先与[14C]腺嘌呤孵育期间标记的豚鼠新皮质和海马切片中引起放射性环AMP的蓄积。H1激动剂2-氨基乙基噻唑在不存在或存在腺苷的情况下，均可抑制新皮质和海马切片中环AMP的蓄积。腺苷的存在增加了对2-氨基乙基噻唑的最大反应，并使EC50降低了近10倍。在不存在腺苷的情况下，2-氨基乙基噻唑的作用在海马切片中被d-溴苯那敏和甲硫米特拮抗，而在存在腺苷的情况下，只有d-溴苯那敏是有效的拮抗剂。在皮质和海马切片中，H2-激动剂4-甲基组胺比2-氨基乙基噻唑引起的环AMP蓄积略小。在存在腺苷的情况下，对4-甲基组胺的反应增强，但明显低于腺苷和2-氨基乙基噻唑组合的反应。在存在腺苷的情况下，海马切片中4-甲基组胺的剂量反应关系似乎由两个部分组成。在不存在腺苷的情况下，对4-甲基组胺的反应被甲硫米特阻断，而在存在腺苷的情况下，该反应被H1和H2-拮抗剂部分阻断。腺苷可显著增加组胺引起的cAMP的蓄积，但EC_（50）并不显著降低。结果表明：（i）H1-和H2-受体均调节中枢神经系统中环AMP-的形成，（ii）腺苷和组胺之间的协同作用主要通过与H1-受体的相互作用介导，（iii）腺苷极大地增加了H1-受体对H1和H2-受体激动剂的亲和力，而不影响其对组胺的亲和力。
—A variety of histamine analogs elicit accumulations of radioactive cyclic AMP in guinea‐pig neocortical and hippocampal slices labelled during a prior incubation with [14C]adenine. The H1agonist, 2‐aminoethylthiazole, elicits accumulation of cyclic AMP in neocortical and hippocampal slices both in the absence or presence of adenosine. The presence of adenosine increases the maximum response to 2‐aminoethylthiazole and decreases the EC50 by nearly 10‐fold. In the absence of adenosine the effects of 2‐aminoethylthiazole are antagonized in hippocampal slices by both d‐brompheniramine and metiamide, while in the presence of adenosine only d‐brompheniramine is an effective antagonist. The H2‐agonist, 4‐methylhistamine, elicits a somewhat smaller accumulation of cyclic AMP than does 2‐aminoethylthiazole in both cortical and hippocampal slices. In the presence of adenosine the response to 4‐methylhistamine is enhanced, but is markedly lower than that seen with the combination of adenosine and 2‐aminoethylthiazole. The dose‐response relationship for 4‐methylhistamine in the presence of adenosine appears in hippocampal slices to consist of two components. The response to 4‐methylhistamine in the absence of adenosine is blocked by metiamide, while in the presence of adenosine the response is partially blocked by both H1 and H2‐antagonists. The accumulation of cyclic AMP elicited by histamine is greatly increased by adenosine but the EC50 is not significantly decreased. The results suggest that (i) both H1‐ and H2‐receptors regulate cyclic AMP‐formation in the central nervous system, (ii) the synergism between adenosine and histamine is mediated primarily by interaction with H1‐receptors and (iii) that adenosine greatly increases the affinity of the H1‐receptors for both H1 and H2‐agonists without affecting its affinity for histamine.