NTS Adenosine Receptors in Cardiovascular Control

描述(申请人提供)：孤束核(NTS)是脑干内心血管内稳态的主要整合中心。NTS接受多种心血管传入，如动脉和心肺压力感受器、外周化学感受器、躯体和内脏传入。这一信息被整合，并通过投射到延髓吻侧和尾侧腹外侧(控制传出交感神经活动)和模糊复合体(控制传出副交感神经活动)，发生自主神经活动的反射控制。NTS内初级传入信息的整合也会受到更高中枢结构的下行投射的显著影响，例如下丘脑内与NTS有相互联系的特定核团。NTS神经元含有丰富的神经递质和神经调节剂，它们可能影响NTS的整合，从而控制心血管系统。最近，我们和其他人已经表明，腺苷显著影响NTS的整合，因此可以在心血管控制方面引发深刻的变化。NTS中的腺苷水平可以通过至少两种不同的机制升高，1)在脑缺血期间，例如在显著的低血压出血或高重力应激期间，2)作为神经递质或辅助递质释放的ATP的分解。腺苷通过A1或A2a受体在突触前发挥作用，可以调节神经递质释放的程度。我们以前的研究强烈支持这样一个概念，即在NTS中工作的不同神经递质/神经调节剂与特定生理和病理情况下的特定模式的局部心血管和交感反应明显相关。一个关键的观察是腺苷在激活支配肾上腺髓质的节前肾上腺交感神经活动中的独特作用。NTS腺苷受体介导的肾上腺髓质激活可能有助于应激期间内环境平衡的恢复，也可能有助于防御反应的不同心血管模式。这种竞争性的更新应用主要集中在1)确定介导NTS腺苷受体亚型刺激反应的机制，以及2)NTS中的腺苷受体在调节下行通路和上行外周输入的心血管反应中的作用。

DESCRIPTION (provided by applicant): The nucleus tractus solitarius (NTS) is the major integrative center within the brainstem for cardiovascular homeostasis. The NTS receives primary input from a variety of cardiovascular afferents such as arterial and cardiopulmonary baroreceptors, peripheral chemoreceptors, somatic and visceral afferents. This information is integrated and via projections to the rostral and caudal ventro-lateral medulla (controlling efferent sympathetic activity) and to the ambiguous complex (controlling efferent parasympathetic activity), reflex control of autonomic nerve activity occurs. Integration of primary afferent information in the NTS can also be markedly affected by descending projections from higher central structures such as specific nuclei within the hypothalamus which have reciprocal connections with the NTS. The NTS neurons contain a rich vocabulary of neurotransmitters and neuromodulators which may affect NTS integration and therefore control of the cardiovascular system. Recently, we and others have shown that adenosine markedly affects NTS integration and thus can elicit profound changes in cardiovascular control. Adenosine levels in the NTS can rise via at least two distinct mechanisms, 1) during cerebral ischemia as occurs, for example, during marked hypotensive hemorrhage or high gravitational stress, and 2) via the breakdown of ATP released as a neurotransmitter or co-transmitter. Adenosine, acting pre-synaptically via both A1 or A2a receptors can modulate the extent of neurotransmitter release. Our previous studies strongly support the concept that different neurotransmitters/neuromodulators operating in the NTS are distinctly linked to specific patterns of regional cardiovascular and sympathetic responses archetypal for specific physiological and pathological situations. A key observation is the unique role of adenosine in the activation of pre-ganglionic adrenal sympathetic nerve activity which innervates the adrenal medulla. NTS adenosine receptor mediated activation of the adrenal medulla likely aids in the restoration of homeostasis during stress as well as likely contributes to the distinct cardiovascular patterns of the defense response. This competing renewal application is focused on 1) determining the mechanisms mediating the responses to stimulation of NTS adenosine receptor subtypes and 2) the role of adenosine receptors in the NTS in modulating cardiovascular responses from descending pathways and ascending peripheral inputs.