Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels.
Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels.
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发表时间：
1994-04
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通讯作者：
M. Endou;E. Poli;R. Levi
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作者：
M. Endou;E. Poli;R. Levi
组胺H3受体在中枢组胺能通路中被发现为抑制性自身受体，也可能调节外周胆碱能和中枢肾上腺素能功能。最近，H3受体被报道抑制豚鼠心房的肾上腺素能变力反应，可能是在连接前位置。我们已经评估了H3介导的心脏肾上腺素能活动的调节是否源于去甲肾上腺素释放的减少。我们发现选择性组胺H3受体激动剂(R)α-甲基组胺能减弱豚鼠心房对肾上腺素能神经末梢跨壁刺激的变力和变时性反应。这种衰减与内源性去甲肾上腺素释放的显著减少有关。相反，(R)α-甲基组胺并不改变外源性去甲肾上腺素的变时性作用。(R)α-甲基组胺对肾上腺素能反应的抑制作用可被选择性H3受体拮抗剂硫代巴比妥钠所阻断，可被百日咳毒素预处理所减弱，并可被N-型钙通道阻滞剂欧米茄毒素所增强，这也可增强肾上腺素能-α2和腺苷-A1受体激动剂的交感神经调节作用。我们的发现表明，交感前组胺H3受体调节豚鼠心肌交感神经末梢的去极化依赖性去甲肾上腺素的释放。这些受体可能与百日咳毒素敏感的Gi/Go蛋白偶联，并可能影响钙电流的减少。我们之前已经报道，交感神经刺激引起心脏组胺的频率依赖性释放，而其他人发现，肾上腺素能活动调节组胺的快速周转池。因此，突触前H3受体可能在心脏肾上腺素能功能中起到调节作用。
Discovered as inhibitory autoreceptors in central histaminergic pathways, histamine H3-receptors may also modulate peripheral cholinergic and central adrenergic function. Recently, H3-receptors were reported to inhibit adrenergic inotropic responses in guinea pig atria, possibly at prejunctional sites. We have assessed whether the H3-mediated modulation of cardiac adrenergic activities results from a reduction in norepinephrine release. We have found that (R) alpha-methylhistamine, the selective histamine H3-receptor agonist, attenuates the inotropic and chronotropic response of isolated guinea pig atria to transmural stimulation of adrenergic nerve endings. This attenuation was associated with a marked reduction in endogenous norepinephrine release. In contrast (R) alpha-methylhistamine did not modify the chronotropic effect of exogenous norepinephrine. The attenuation of adrenergic responses by (R) alpha-methylhistamine was 1) prevented by thioperamide, the selective H3-receptor antagonist; 2) attenuated by pertussis-toxin pretreatment and 3) potentiated by the N-type Ca(++)-channel blocker omega-conotoxin, which also potentiated the sympathetic modulatory effects of adrenergic-alpha 2 and adenosine-A1 receptor agonists. Our findings indicate that prejunctional histamine H3-receptors modulate the depolarization-dependent norepinephrine release from sympathetic nerve endings in the guinea pig myocardium. These receptors are probably coupled to a pertussis-toxin-sensitive Gi/Go protein and probably effect a reduction in Ca++ current. We have previously reported that sympathetic stimulation elicits a frequency-dependent release of cardiac histamine, whereas others had found that adrenergic activity regulates histamine's rapid turnover pool. Accordingly, presynaptic H3-receptors are likely to serve a modulatory role in cardiac adrenergic function.