Integrative studies on the control of circulation and respiration.

循环、通风和新陈代谢之间的合作是维持生命所必需的。本研究的目的是对循环、通气和代谢功能进行同步和综合评估，并阐明控制这些功能的机制。为此，我们开发了1)在没有麻醉的情况下同时测量循环（血压，心率等）的系统，2)x射线电视系统和微血管成像技术，用于测量进入器官实质的小血管（直径50μm）的局部循环，3)同步加速器x射线衍射技术，用于实时分析原位弹射大鼠心脏的心肌过桥循环。我们将第一个系统应用于前列环素（PGI_2） KO小鼠，发现PGI_2可能对血管舒缩张力有重要的控制作用，但在正常氧合或急性缺氧时对通气和代谢的控制作用不显著。然而，我们首次发现，在没有No（所有亚型）和PGI_2的情况下，正常的化学反射通气和心率反应几乎被消除。我们证实神经元NO在增强通气和控制外周血管舒张中起着最重要的作用。另一方面，PGI_2增强α_2-肾上腺素能受体介导的缺氧时交感神经活动的抑制，因此是缺血时心率的重要调节因子。我们还将该系统应用于M_2-毒蕈碱乙酰胆碱受体KO小鼠，发现迷走性心动过缓和呼吸性窦性心律失常主要是由M_2受体介导的，而起动时和动态运动时的心脏加速不是由M_2受体介导的。我们的数据表明，副交感神经成分在降低HR表激活水平方面起着更重要的作用。通过对慢性缺氧大鼠的二次血管造影系统和技术，我们发现缺氧诱导的内皮和可溶一氧化氮合酶（NOS）的上调有助于减轻小肌肉动脉（<300μm直径）的缺氧性肺血管收缩，从而抑制肺动脉高压的进展。我们将第三种技术应用于自发跳动的大鼠心脏左心室自由壁，发现在非缺血区域收缩期间，质量传递先于晶格间距的增加。左冠状动脉闭塞消除了肌球蛋白晶格间距的增加，并严重减少了缺血区域的物质传递。这项技术将允许实时的原位分析区域过桥动力学，也可能有助于研究钙循环在心室输出调节中的Frank-Starling机制

Cooperation between circulation, ventilation and metabolism is necessary for he maintenance of life. The purpose of this study was to perform simultaneous and integrative assessment of circulatory, ventilatory and metabolic functions and clarify the mechanisms for controlling these functions. To this end, we have developed 1)a system for simultaneous measurement of circulatory (blood pressure, heart rate etc.), ventilatoty in unrestrained mice in the absence of anesthesia, 2)an X-ray television system and microangiographic techniques for measuring the local circulation in small vessels ( 50μm diameter) that run into organ parenchyma and 3) synchrotron X-ray diffraction technique for analyzing myocardial crossbridge cycling in situ ejecting rat hearts in real time.We have applied he first system to prostacyclin (PGI_2) KO mice and found that although PGI_2 might be important for the control of vasomotor tone it plays no significant role in the control of ventilation or metabolism during … More normoxia or acute hypoxia. However, for the first time we show that normal chemoreflex ventilatory and heart rate responses were nearly abolished in the absence of both No (all isoforms) and PGI_2. We verified that neuronal NO plays the most important role in enhancing ventilation, as well as controlling peripheral vasodilatation. On the other hand, PGI_2 enhances α_2-adrenergic receptor mediated inhibition of sympathetic activity during hypoxia and is therefore an important regulator of heart rate during ischemia.We have also applied this system to M_2-muscarinic acetylcholine receptor KO mice and found that vagal bradycardia and the respiratory sinus arrhythmia in the inactive state are chiefly mediated by the M_2 receptor, whereas cardiac acceleration at the onset and during dynamic exercise is not solely mediated by it. Our data indicate that the parasympathetic component plays a more important role in lowering HR form activated levels.Using the second angiographic system and technique on chronically-hypoxic rats, we found that hypoxia-induced upregulation of endothelial and iducible nitric oxide synthase (NOS) contributes to attenuating hypoxic pulmonary vasoconstriction in the small muscular arteries (<300μm diam.) and, in turn, inhibit the progress of pulmonary hypertension.We have applied the third technique to the left ventricle free wall of spontaneously beating rat hearts and found that mass transfer preceded increases in lattice spacing during systole in non-ischemic regions. Left coronary occlusion eliminated myosin lattice spacing increases and severely reduced mass transfer in the ischemic region. This technique will permit real time in situ analysis of regional crossbridge dynamics that might also facilitate investigations of calcium cycling in ventricular output regulation by the Frank-Starling mechanism Less