| Project/Area Number |
13670053
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
SHIRAI Mikiyasu National Cardiovasc.Center Research Institute, Dept.of Cardiac Physiol., senior staff, 心臓生理部, 室長 (70162758)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIURA Naoki National Cardiovasc.Center Research Institute, Dept.of Cardiac Physiol., staff, 心臓生理部, 室員 (70132933)
SHIMOUCHI Akito National Cardiovasc.Center Research Institute, Dept.of Cardiovasc.Dynamics, staff, 循環機能動態部, 室員 (80211291)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | telemetry / prostacyclin KO mouse / muscarinic receptor KO mouse / microangiography / hypoxic pulmonary vasoconstriction / adrenomedullin / synchrotron X-ray diffraction / cardiac crossbridge dynamics / ムスカリン性アセチルコリン受容体 / M_2ノックアウトマウス / 心拍変動 / 呼吸性変動 / 運動 / 低酸素 / 化学受容器反射 / 神経型一酸化窒素合成酵素 / α_2アドレナリン受容体 / 心拍応答 / 換気応答 / 覚醒下無拘束小動物 / 呼吸機能 / 酸素消費量 / 二酸化炭素排出量 / 微小血管造影 |
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| Research Abstract |
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
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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
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