Buttgereit Jens, Shanks Julia, Li Dan, Hao Guoliang, Athwal Arvinder, Langenickel Thomas H, Wright Hannah, da Costa Goncalves Andrey C, Monti Jan, Plehm Ralph, Popova Elena, Qadri Fatimunnisa, Lapidus Irina, Ryan Brent, Özcelik Cemil, Paterson David J, Bader Michael, Herring Neil
Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine (MDC) and the Charité Medical Faculty, Berlin, Germany.
Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
Cardiovasc Res. 2016 Dec;112(3):637-644. doi: 10.1093/cvr/cvw184. Epub 2016 Aug 5.
B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPR-A) receptor signalling inhibits cardiac sympathetic neurotransmission, although C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesized that CNP acts similarly to BNP, and that transgenic rats (TGRs) with neuron-specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive.
Mean arterial pressure and heart rate (HR) were significantly (P < 0.05) elevated in freely moving TGRs (n = 9) compared with Sprague Dawley (SD) controls (n = 10). TGR had impaired left ventricular systolic function and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats, CNP (250 nM, n = 8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7 Hz) in vitro whereas the response to bath-applied norepinephrine (NE, 1 μM, n = 6) remained intact. CNP (250 nM, n = 8) significantly reduced the release of H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250 nM, n = 6). The neuronal Ca current (n = 6) and intracellular Ca transient (n = 9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n = 9) with the sympatholytic clonidine (125 µg/kg per day) significantly reduced mean arterial pressure and HR to levels observed in the SD (n = 9).
C-type natriuretic peptide reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP-NPR-B signalling lead to hypertension, tachycardia, and impaired left ventricular systolic function secondary to sympatho-excitation.
B型利钠肽（BNP）-利钠肽受体A（NPR-A）受体信号传导可抑制心脏交感神经传递，尽管C型利钠肽（CNP）是神经系统中主要的神经肽，在心脏和血管系统中均有表达。我们推测CNP的作用与BNP相似，并且神经元特异性过表达显性负性NPR-B受体的转基因大鼠（TGR）会出现交感神经驱动增强。
与Sprague Dawley（SD）对照大鼠（n = 10）相比，自由活动的TGR（n = 9）的平均动脉压和心率（HR）显著升高（P < 0.05）。TGR的左心室收缩功能受损，HR变异性的频谱分析表明向交感神经兴奋转变。免疫组织化学显示星状神经节神经元中NPR-B与酪氨酸羟化酶共染色。在SD大鼠中，CNP（250 nM，n = 8）可显著降低体外右侧星状神经节刺激（1-7 Hz）期间的心动过速，而对浴加去甲肾上腺素（NE，1 μM，n = 6）的反应保持不变。CNP（250 nM，n = 8）可显著降低离体心房中H-NE的释放，而NPR-B拮抗剂P19（250 nM，n = 6）可阻止这种释放。在离体星状神经元中，CNP也可降低神经元钙电流（n = 6）和细胞内钙瞬变（n = 9，使用fura-2AM）。用抗交感神经药可乐定（每天125 µg/kg）治疗TGR（n = 9）可使平均动脉压和HR显著降低至SD大鼠（n = 9）中观察到的水平。
C型利钠肽通过减少神经元钙信号传导和通过NPR-B受体释放NE来降低心脏交感神经传递。损害CNP-NPR-B信号传导的情况会导致高血压、心动过速以及继发于交感神经兴奋的左心室收缩功能受损。
