Activation of histamine H-3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia - Comparison with adenosine A(1)-receptors and alpha(2)-adrenoceptors
Activation of histamine H-3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia - Comparison with adenosine A(1)-receptors and alpha(2)-adrenoceptors
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DOI：
10.1161/01.res.78.3.475
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发表时间：
1996-03-01
影响因子：
20.1
通讯作者：
Levi, R
中科院分区：
文献类型：
--
作者：
Imamura, M;Lander, HM;Levi, R
我们以前的研究表明，连接前组胺H-3受体下调去甲肾上腺素的胞吐作用，这种作用在早期心肌缺血中明显增强。在本研究中，我们调查是否H-3受体调节非胞吐去甲肾上腺素释放在长期心肌缺血。在这种情况下，交感神经末梢中pH（i）的降低依次导致Na+-H+反向转运蛋白（NHE）的代偿性激活、细胞内Na+的积累、去甲肾上腺素的神经元摄取的逆转，以及因此载体介导的去甲肾上腺素的释放。因此，去甲肾上腺素摄取和NHE抑制剂地昔帕明（10 nmol/L）和5-（N-乙基-N-异丙基）-阿米洛利（ETPA，10 μ mol/L）分别使离体豚鼠心脏经历20分钟全脑缺血和45分钟再灌注后的去甲肾上腺素溢出减少约80%和70%。H-3受体激动剂imetit（0.1 μ mol/L）可使载体介导的去甲肾上腺素释放降低约50%。这种作用被H-3受体拮抗剂硫代哌丁胺（0.3 μ mol/L）阻断，表明H-3受体激活抑制载体介导的去甲肾上腺素释放。在较低浓度下，imetit（10 nmol/L）或EIPA（3 μ mol/L）不抑制载体介导的去甲肾上腺素释放。然而，imetit（10 nmol/L）和EIPA（3 μ mol/L）联合使用时，抑制率为25%。这种协同作用表明H-3受体和NHE之间的关联。可以想象，H-3-受体的激活可能导致NHE的抑制。事实上，已知刺激NHE的α 2-肾上腺素受体激活可增强去甲肾上腺素的释放，而α 2-肾上腺素受体阻断可减弱去甲肾上腺素的释放。此外，腺苷A（1）受体的激活可显著减弱去甲肾上腺素的释放，而腺苷A（1）受体的抑制可增强去甲肾上腺素的释放。由于去甲肾上腺素的释放与再灌注心律失常的严重程度直接相关，而伊美替可使心室颤动的发生率降低50%，我们对H-3受体激动剂的研究结果可能会进一步发展新的药理学手段，以减少临床环境中的再灌注心律失常。
We previously showed that prejunctional histamine H-3-receptors downregulate norepinephrine exocytosis, which is markedly enhanced in early myocardial ischemia. In the present study, we investigated whether H-3-receptors modulate nonexocytotic norepinephrine release during protracted myocardial ischemia. In this setting, decreased pH(i) in sympathetic nerve endings sequentially leads to a compensatory activation of the Na+-H+ antiporter (NHE), accumulation of intracellular Na+, reversal of the neuronal uptake of norepinephrine, and thus carrier-mediated release of norepinephrine. Accordingly, norepinephrine overflow from isolated guinea pig hearts undergoing 20-minute global ischemia and 45-minute reperfusion was attenuated approximate to 80% by desipramine (10 nmol/L) and 70% by 5-(N-ethyl-N-isopropyl)-amiloride (ETPA, 10 mu mol/L), inhibitors of norepinephrine uptake and NHE, respectively. The H-3-receptor agonist imetit (0.1 mu mol/L) decreased carrier-mediated norepinephrine release by approximate to 50%. This effect was blocked by the H-3-receptor antagonist thioperamide (0.3 mu mol/L), indicating that H-3-receptor activation inhibits carrier-mediated norepinephrine release. At lower concentrations, imetit (10 nmol/L) or EIPA (3 mu mol/L) did not inhibit carrier-mediated norepinephrine release. However, a 25% inhibition occurred with imetit (10 nmol/L) and EIPA (3 mu mol/L) combined. This synergism suggests an association between H-3-receptors and NHE. Conceivably, activation of H-3-receptors may lead to inhibition of NHE. In fact, alpha 2-adrenoceptor activation, which is known to stimulate NHE enhanced norepinephrine release, whereas alpha 2-adrenoceptor blockade attenuated it. Furthermore, activation of adenosine A(1)-receptors markedly attenuated norepinephrine release, whereas their inhibition potentiated it. Because norepinephrine release directly correlated with the severity of reperfusion arrhythmia and imetit reduced the incidence of ventricular fibrillation by 50%, our findings with H-3-receptor agonists may further the development of novel pharmacological means to reduce reperfusion arrhythmias in the clinical setting.