环磷酸腺苷（cAMP）和钾离子（K⁺）通道依赖性机制在仔猪缺氧/缺血性损伤中孤啡肽/孤啡肽FQ诱导的脑血管舒张中的作用

Role of cAMP and K(+) channel-dependent mechanisms in piglet hypoxic/ischemic impaired nociceptin/orphanin FQ-induced cerebrovasodilation.

作者信息

Ben-Haim G, Armstead W M

机构信息

Departments of Anesthesia and Pharmacology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.

出版信息

Brain Res. 2000 Nov 24;884(1--2):51-8. doi: 10.1016/s0006-8993(00)02882-1.

DOI:10.1016/s0006-8993(00)02882-1

PMID:11082486

Abstract

This study was designed to determine the role of altered cAMP and K(+) channel-dependent mechanisms in impaired pial artery dilation to the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ) following hypoxia/ischemia in newborn pigs equipped with a closed cranial window. Recent studies have observed that NOC/oFQ elicits pial dilation via release of cAMP, which, in turn, activates the calcium sensitive (K(ca)) and the ATP-dependent K(+) (K(ATP)) channel. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased pO(2) to 35+/-3 mm Hg with unchanged pCO(2). Topical NOC/oFQ (10(-8), 10(-6) M) induced vasodilation was attenuated by ischemia/reperfusion (I+R) and reversed to vasoconstriction by hypoxia/ischemia/reperfusion (H+I+R) at 1 h of reperfusion (control, 9+/-1 and 16+/-1%; I+R, 3+/-1 and 6+/-1%; H+I+R, -7+/-1 and -12+/-1%). Such altered dilation returned to control values within 4 h in I+R animals and within 12 h in H+I+R animals. NOC/oFQ dilation was associated with elevated CSF cAMP in control animals but such biochemical changes were attenuated in I+R animals and reversed to decreases in cAMP concentration in H+I+R animals (control, 1037+/-58 and 1919+/-209 fmol/ml; I+R, 1068+/-33 and 1289+/-30 fmol/ml; H+I+R, 976+/-36 and 772+/-27 fmol/ml for absence and presence of NOC/oFQ 10(-6) M, respectively). Topical 8-Bromo cAMP (10(-8), 10(-6) M) pial dilation was unchanged by I+R but blunted by H+I+R (control, 10+/-1 and 20+/-1%; I+R, 11+/-1 and 20+/-2%; H+I+R, 0+/-1 and 0+/-2%). Pituitary adenylate cyclase activating polypeptide and cromakalim, adenylate cyclase and K(ATP) channel activators, respectively, elicited dilation that was blunted by both I+R and H+I+R while NS1619, a K(ca) channel activator, elicited dilation that was unchanged by I+R but blunted by H+I+R. These data indicate that impaired NOC/oFQ dilation following I+R results form altered adenylate cyclase and K(ATP) channel-dependent mechanisms. These data further indicate that impaired NOC/oFQ dilation following H+I+R results not only from altered adenylate cyclase and K(ATP) channel but also from altered cAMP and K(ca) channel-dependent mechanisms.

摘要

本研究旨在确定在配备封闭颅窗的新生猪缺氧/缺血后，环磷酸腺苷（cAMP）和钾（K⁺）通道依赖性机制改变在软脑膜动脉对新发现的阿片样物质孤啡肽/孤啡肽FQ（NOC/oFQ）扩张受损中的作用。最近的研究观察到，NOC/oFQ通过释放cAMP引起软脑膜扩张，进而激活钙敏感性钾（Kca）通道和ATP依赖性钾（KATP）通道。通过升高颅内压诱导全脑缺血（20分钟），而缺氧（10分钟）将动脉血氧分压（pO₂）降至35±3 mmHg，动脉血二氧化碳分压（pCO₂）不变。在再灌注1小时时，局部应用NOC/oFQ（10⁻⁸、10⁻⁶ M）诱导的血管舒张被缺血/再灌注（I+R）减弱，并被缺氧/缺血/再灌注（H+I+R）逆转至血管收缩（对照组，9±1%和16±1%；I+R组，3±1%和6±1%；H+I+R组，-7±1%和-12±1%）。这种改变的舒张在I+R动物中4小时内恢复到对照值，在H+I+R动物中12小时内恢复到对照值。在对照动物中，NOC/oFQ舒张与脑脊液cAMP升高有关，但这种生化变化在I+R动物中减弱，在H+I+R动物中逆转至cAMP浓度降低（对照组，分别在不存在和存在10⁻⁶ M NOC/oFQ时为1037±58和1919±209 fmol/ml；I+R组，1068±33和1289±30 fmol/ml；H+I+R组，976±36和772±27 fmol/ml）。局部应用8-溴环磷酸腺苷（10⁻⁸、10⁻⁶ M）引起的软脑膜舒张在I+R时未改变，但在H+I+R时减弱（对照组，10±1%和20±1%；I+R组，11±1%和20±2%；H+I+R组，0±1%和0±2%）。垂体腺苷酸环化酶激活多肽和克罗卡林分别为腺苷酸环化酶和KATP通道激活剂，它们引起的舒张在I+R和H+I+R时均减弱，而Kca通道激活剂NS1619引起的舒张在I+R时未改变，但在H+I+R时减弱。这些数据表明，I+R后NOC/oFQ舒张受损是由于腺苷酸环化酶和KATP通道依赖性机制改变所致。这些数据进一步表明，H+I+R后NOC/oFQ舒张受损不仅是由于腺苷酸环化酶和KATP通道改变，还由于cAMP和Kca通道依赖性机制改变。