Ellis E F, Holt S A, Wei E P, Kontos H A
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Am J Physiol. 1988 Aug;255(2 Pt 2):H397-400. doi: 10.1152/ajpheart.1988.255.2.H397.
Previous studies have shown that after experimental neural trauma or acute hypertension the brain produces superoxide anion radicals, and brain arterioles display endothelial lesions, dilation, and loss of normal reactivity in response to a decrease in CO2 tension. Because these abnormalities are prevented by pretreatment with free radical scavengers or inhibitors of the cyclooxygenase component of prostaglandin (PG) H synthase, arachidonic acid metabolism by PGH synthase with concomitant formation of tissue injuring oxygen radicals causes the vascular damage. The purpose of the present experiments was to determine whether kinins, which are known to stimulate arachidonate metabolism and to induce cerebral arteriolar dilation via production of superoxide anion, may be involved in initiating the cerebrovascular abnormalities produced by neural trauma in cats. The diameter and reactivity of untreated in vivo pial arterioles on one cerebral cortex was compared with the diameter and reactivity of pial arterioles on the contralateral cortex, which were pretreated topically with a competitive receptor antagonist, which is specific for kinins. Before fluid percussion neural trauma was induced, arterioles on both cerebral hemispheres constricted normally to a decrease in CO2 tension. After injury, the arterioles on the untreated cortex dilated and did not constrict in response to a decrease in arterial CO2 tension, whereas the arterioles pretreated with the kinin antagonist dilated less and displayed normal reactivity to CO2. These experiments demonstrate that a specific kinin receptor stimulates PGH synthase-dependent, free radical-mediated cerebrovascular injury. Given the ubiquitous distribution of the kallikrein-kinin system, we propose that kinins may be an important common mediator of systemic vascular injury and abnormal vascular reactivity.
先前的研究表明，在实验性神经创伤或急性高血压后，大脑会产生超氧阴离子自由基，脑小动脉会出现内皮损伤、扩张，并且在二氧化碳张力降低时丧失正常反应性。由于这些异常可通过自由基清除剂或前列腺素（PG）H合酶环氧化酶成分抑制剂的预处理来预防，因此PGH合酶介导的花生四烯酸代谢以及伴随组织损伤性氧自由基的形成会导致血管损伤。本实验的目的是确定激肽是否参与引发猫神经创伤所致的脑血管异常，已知激肽可刺激花生四烯酸代谢并通过产生超氧阴离子诱导脑小动脉扩张。将一侧大脑皮质未经处理的体内软脑膜小动脉的直径和反应性与对侧皮质经局部用激肽特异性竞争性受体拮抗剂预处理的软脑膜小动脉的直径和反应性进行比较。在诱导流体冲击性神经创伤之前，两侧大脑半球的小动脉在二氧化碳张力降低时正常收缩。损伤后，未经处理的皮质上的小动脉扩张，并且在动脉二氧化碳张力降低时不收缩，而用激肽拮抗剂预处理的小动脉扩张程度较小，并且对二氧化碳表现出正常反应性。这些实验表明，特异性激肽受体刺激PGH合酶依赖性、自由基介导的脑血管损伤。鉴于激肽释放酶-激肽系统广泛分布，我们认为激肽可能是全身血管损伤和异常血管反应性的重要共同介质。
