Role of CO in Cerebrovascular EDHF-mediated Dilation

描述（由申请人提供）：一氧化碳（CO）由血红素加氧酶（HO）内源性产生，CO可能是包括脑血管在内的血管系统中的重要信号分子。内皮源性超极化因子（Endothelium-derived hyperpolarization factor，EDHF）具有舒张血管的作用，在阻力血管中的作用可能超过一氧化氮（nitric oxide，NO）。EDHF也可能有助于在NO减少的疾病条件下保持血管功能。该建议将研究CO在EDHF介导的脑动脉扩张中的作用。我的初步数据表明，用Cr（III）中卟啉IX（CrMP）抑制HO阻断了大鼠大脑中动脉（MCA）中EDHF介导的DTP扩张。在大鼠MCA中，CO本身不是扩张剂，然而，在CrMP的存在下，外源性CO恢复EDHF介导的扩张。这些数据表明，CO在EDHF介导的扩张中起着允许的作用。该建议将检查CO对大鼠MCA血管舒张重要的条件，并将开始检查CO影响大鼠MCA EDHF介导的扩张的机制。因此，这一建议首次将CO和EDHF这两个重要的研究领域结合在一起。

DESCRIPTION (provided by applicant): Carbon monoxide (CO) is endogenously produced by heme oxygenase (HO) and CO may be an important signaling molecule in the vasculature including cerebral vessels. Endothelium-derived hyperpolarization factor (EDHF) relaxes blood vessels and may predominate over nitric oxide (NO) in resistance sized vessels. EDHF may also help to preserve vascular function in disease conditions where NO is reduced. This proposal will examine the role of CO in EDHF-mediated dilation in cerebral arteries. My preliminary data demonstrate that inhibition of HO with Cr(lll) mesoporphyrin IX (CrMP) blocks EDHF-mediated dilation to DTP in the rat middle cerebral artery (MCA). In the rat MCA, CO itself is not a dilator, however, in the presence of CrMP, exogenous CO restores EDHF-mediated dilation. These data suggest that CO plays a permissive-like role in EDHF-mediated dilation. This proposal will examine conditions in which CO is important for vasodilation in the rat MCA and will begin to examine the mechanism by which CO influences EDHF-mediated dilation in the rat MCA. Thus, this proposal brings together, for the first time, two important fields of study, CO and EDHF.