Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
J Pharmacol Exp Ther. 2012 Jan;340(1):185-91. doi: 10.1124/jpet.111.187765. Epub 2011 Oct 19.
In severe myocardial ischemia, histamine 3 (H₃) receptor activation affords cardioprotection by preventing excessive norepinephrine release and arrhythmias; pivotal to this action is the inhibition of neuronal Na⁺/H⁺ exchanger (NHE). Conversely, angiotensin II, formed locally by mast cell-derived renin, stimulates NHE via angiotensin II type 1 (AT₁) receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the NHE-modulating effects of H₃ receptors and AT₁ receptors. The purpose of this investigation was therefore to elucidate the H₃/AT₁ receptor interaction in myocardial ischemia/reperfusion. We found that H₃ receptor blockade with clobenpropit increased norepinephrine overflow and arrhythmias in Langendorff-perfused guinea pig hearts subjected to ischemia/reperfusion. This coincided with increased neuronal AT₁ receptor expression. NHE inhibition with cariporide prevented both increases in norepinephrine release and AT₁ receptor expression. Moreover, norepinephrine release and AT₁ receptor expression were increased by the nitric oxide (NO) synthase inhibitor N(G)-methyl-L-arginine and the protein kinase C activator phorbol myristate acetate. H₃ receptor activation in differentiated sympathetic neuron-like PC12 cells permanently transfected with H₃ receptor cDNA caused a decrease in protein kinase C activity and AT₁ receptor protein abundance. Collectively, our findings suggest that neuronal H₃ receptor activation inhibits NHE by diminishing protein kinase C activity. Reduced NHE activity sequentially causes intracellular acidification, increased NO synthesis, and diminished AT₁ receptor expression. Thus, H₃ receptor-mediated NHE inhibition in ischemia/reperfusion not only opposes the angiotensin II-induced stimulation of NHE in cardiac sympathetic neurons, but also down-regulates AT₁ receptor expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias.
在严重的心肌缺血中，组胺 3（H₃）受体的激活通过防止去甲肾上腺素过度释放和心律失常来提供心脏保护；这一作用的关键是抑制神经元 Na⁺/H⁺交换器（NHE）。相反，由肥大细胞衍生的肾素形成的血管紧张素 II 通过血管紧张素 II 型 1（AT₁）受体刺激 NHE，促进去甲肾上腺素释放和心律失常。因此，缺血性功能障碍可能取决于 H₃受体和 AT₁受体对 NHE 调节作用的平衡。因此，本研究的目的是阐明心肌缺血/再灌注中的 H₃/AT₁ 受体相互作用。我们发现，用克洛苯丙肽阻断 H₃ 受体可增加 Langendorff 灌注豚鼠心脏缺血/再灌注时的去甲肾上腺素溢出和心律失常。这与神经元 AT₁ 受体表达增加同时发生。用 cariporide 抑制 NHE 可防止去甲肾上腺素释放和 AT₁ 受体表达的增加。此外，一氧化氮（NO）合酶抑制剂 N(G)-甲基-L-精氨酸和蛋白激酶 C 激活剂佛波醇肉豆蔻酸乙酯增加去甲肾上腺素释放和 AT₁ 受体表达。在永久性转染 H₃ 受体 cDNA 的分化交感神经元样 PC12 细胞中激活 H₃ 受体可降低蛋白激酶 C 活性和 AT₁ 受体蛋白丰度。总的来说，我们的发现表明神经元 H₃ 受体激活通过降低蛋白激酶 C 活性来抑制 NHE。NHE 活性降低会导致细胞内酸化、NO 合成增加和 AT₁ 受体表达减少。因此，缺血/再灌注中 H₃ 受体介导的 NHE 抑制不仅拮抗心脏交感神经元中血管紧张素 II 诱导的 NHE 刺激，还下调 AT₁ 受体表达。心脏保护最终源自血管紧张素 II 和去甲肾上腺素作用的综合减弱以及心律失常的缓解。
