Georgia Health Sciences University, Department of Physiology, 1120 15th St, Augusta, GA 30912, USA.
Hypertension. 2011 Sep;58(3):454-63. doi: 10.1161/HYPERTENSIONAHA.111.175810. Epub 2011 Aug 8.
Neurohumoral activation, a hallmark in heart failure (HF), is linked to the progression and mortality of HF patients. Thus, elucidating its precise underlying mechanisms is of critical importance. Other than its classic peripheral vasodilatory actions, the gas NO is a pivotal neurotransmitter in the central nervous system control of the circulation. While accumulating evidence supports a contribution of blunted NO function to neurohumoral activation in HF, the precise cellular sources, and NO synthase (NOS) isoforms involved, remain unknown. Here, we used a multidisciplinary approach to study the expression, cellular distribution, and functional relevance of the endothelial NOS isoform within the hypothalamic paraventricular nucleus in sham and HF rats. Our results show high expression of endothelial NOS in the paraventricular nucleus (mostly confined to astroglial cells), which contributes to constitutive NO bioavailability, as well as tonic inhibition of presympathetic neuronal activity and sympathoexcitatory outflow from the paraventricular nucleus. A diminished endothelial NOS expression and endothelial NOS-derived NO availability were found in the paraventricular nucleus of HF rats, resulting, in turn, in blunted NO inhibitory actions on neuronal activity and sympathoexcitatory outflow. Taken together, our study supports blunted central nervous system endothelial NOS-derived NO as a pathophysiological mechanism underlying neurohumoral activation in HF.
神经体液激活是心力衰竭（HF）的一个标志，与 HF 患者的进展和死亡率有关。因此，阐明其确切的潜在机制至关重要。除了其经典的外周血管舒张作用外，气体 NO 还是中枢神经系统对血液循环控制的关键神经递质。虽然越来越多的证据支持 NO 功能减弱对 HF 中神经体液激活的贡献，但确切的细胞来源和涉及的一氧化氮合酶（NOS）同工型仍不清楚。在这里，我们使用多学科方法研究了内皮型一氧化氮合酶同工型在假手术和 HF 大鼠下丘脑室旁核中的表达、细胞分布和功能相关性。我们的研究结果表明，内皮型一氧化氮合酶在室旁核中高表达（主要局限于星形胶质细胞），这有助于维持 NO 的生物利用度，以及对交感神经节前神经元活动和室旁核中交感神经兴奋传出的紧张性抑制。在 HF 大鼠的室旁核中发现内皮型一氧化氮合酶表达减少和内皮型一氧化氮合酶衍生的 NO 可用性降低，从而导致 NO 对神经元活动和交感神经兴奋传出的抑制作用减弱。综上所述，我们的研究支持中枢神经系统内皮型一氧化氮合酶衍生的 NO 减弱是 HF 中神经体液激活的病理生理机制。
