Koch Henner, Caughie Cali, Elsen Frank P, Doi Atsushi, Garcia Alfredo J, Zanella Sebastien, Ramirez Jan-Marino
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, 98101, USA; Department of Neurological Surgery, University of Washington, Seattle, WA, 98104, USA; Department of Neurology, University of Tübingen, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
J Physiol. 2015 Jan 1;593(1):305-19. doi: 10.1113/jphysiol.2014.279794. Epub 2014 Nov 3.
Prostaglandin E2 (PGE2) augments distinct inspiratory motor patterns, generated within the preBötzinger complex (preBötC), in a dose-dependent way. The frequency of sighs and gasping are stimulated at low concentrations, while the frequency of eupnoea increases only at high concentrations. We used in vivo microinjections into the preBötC and in vitro isolated brainstem slice preparations to investigate the dose-dependent effects of PGE2 on the preBötC activity. Synaptic measurements in whole cell voltage clamp recordings of inspiratory neurons revealed no changes in inhibitory or excitatory synaptic transmission in response to PGE2 exposure. In current clamp recordings obtained from inspiratory neurons of the preBötC, we found an increase in the frequency and amplitude of bursting activity in neurons with intrinsic bursting properties after exposure to PGE2. Riluzole, a blocker of the persistent sodium current, abolished the effect of PGE2 on sigh activity, while flufenamic acid, a blocker of the calcium-activated non-selective cation conductance, abolished the effect on eupnoeic activity caused by PGE2. Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E2 (PGE2) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBötzinger complex (preBötC), a medullary area that is critical for breathing. Low concentrations of PGE2 (100-300 nm) increased the sigh frequency, while higher concentrations (1-2 μm) were required to increase the eupnoeic frequency. The concentration-dependent effects were similarly observed in the isolated preBötC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current (INap), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium-activated non-selective cation conductance (ICAN ) abolished the effect of PGE2 on fictive eupnoea at higher concentrations. At the cellular level PGE2 significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE2 affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE2 differentially modulates sigh, gasping and eupnoeic activity by differentially increasing INap and ICAN currents in preBötC neurons.
前列腺素E2（PGE2）以剂量依赖性方式增强在脑桥前包钦格复合体（preBötC）内产生的不同吸气运动模式。低浓度时刺激叹息和喘息的频率，而仅在高浓度时潮式呼吸频率增加。我们通过向preBötC进行体内微量注射以及体外分离脑干切片制备，来研究PGE2对preBötC活动的剂量依赖性效应。在吸气神经元的全细胞电压钳记录中的突触测量显示，暴露于PGE2后抑制性或兴奋性突触传递无变化。在从preBötC的吸气神经元获得的电流钳记录中，我们发现暴露于PGE2后，具有固有爆发特性的神经元爆发活动的频率和幅度增加。利鲁唑，一种持续性钠电流阻滞剂，消除了PGE2对叹息活动的影响，而氟芬那酸，一种钙激活非选择性阳离子电导阻滞剂，消除了PGE2对潮式呼吸活动的影响。前列腺素是哺乳动物机体自主功能的重要调节因子。在此我们在体内证明，当将前列腺素E2（PGE2）注入对呼吸至关重要的延髓区域脑桥前包钦格复合体（preBötC）时，它可不同程度地增加潮式呼吸（正常呼吸）和叹息（增强呼吸）的频率。低浓度的PGE2（100 - 300 nM）增加叹息频率，而需要更高浓度（1 - 2 μM）来增加潮式呼吸频率。在分离的preBötC中同样观察到浓度依赖性效应。这种体外制备还显示，利鲁唑，一种持续性钠电流（INap）阻滞剂，消除了对叹息的调节作用，而氟芬那酸，一种钙激活非选择性阳离子电导（ICAN）拮抗剂，在较高浓度时消除了PGE2对虚拟潮式呼吸的影响。在细胞水平，PGE2显著增加吸气神经元固有爆发的幅度和频率。相比之下，PGE2既不影响兴奋性也不影响抑制性突触传递。我们得出结论，PGE2通过不同程度地增加preBötC神经元中的INap和ICAN电流，来不同程度地调节叹息、喘息和潮式呼吸活动。
