Palmer G C, Christie-Pope B C, Medina M A, Colombo P M, Palmer S J
CV/CNS Pharmacology, Pennwalt Corporation, Rochester, New York 14623.
Metab Brain Dis. 1988 Sep;3(3):161-77. doi: 10.1007/BF00999233.
The present study was an extension of earlier work regarding the role of cyclic nucleotides and related enzymes during cerebral ischemia in the gerbil. Following unilateral carotid occlusion, levels of cyclic AMP and cyclic GMP were measured in four rapidly inactivated brain regions at 3, 6, and 24 hr after permanent occlusion and at 2 hr of occlusion plus 1 hr of reflow. An analysis of variance indicated significant minor fluctuations in the steady-state levels of the two cyclic nucleotides within the frontal cortex, the hippocampus, the striatum, and especially the olfactory tubercle with respect to occlusion time (3 and 24 hr) but not when comparing control vs ischemic hemispheres (except at 3 hr). Changes occurred only in animals developing neurological symptoms of ischemia. At 24 hr postocclusion the specific activity of the low-Km form of cyclic AMP phosphodiesterase was elevated especially on the ischemic side when determined in homogenates of the four brain regions. Alternatively, the high-Km form of the enzyme in the presence or absence of Ca2+-calmodulin was unchanged. Guanylate cyclase activity in tissue homogenates was not influenced by the conditions of ischemia until 24 hr had elapsed, an event likewise unique to symptomatic gerbils. The sensitivity of the enzyme to hematin-catalase was decreased in the ischemic hemispheres of the hippocampus, striatum, and olfactory tubercle. In addition, further activation of the hematin-catalase response by NaN3 was depressed in the ischemic side of the hippocampus and striatum. Taken together these and previous studies indicate that fluctuations in the steady-state levels of cyclic nucleotides that occur rather prominently during acute and to a lesser degree during prolonged ischemia are not correlated with associated changes in enzymes responsible for their synthesis and/or degradation.
本研究是早期关于沙鼠脑缺血期间环核苷酸及相关酶作用研究的扩展。在单侧颈动脉闭塞后，于永久闭塞后3小时、6小时和24小时以及闭塞2小时加再灌注1小时时，测量了四个快速失活脑区的环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）水平。方差分析表明，额叶皮质、海马体、纹状体，尤其是嗅结节中，这两种环核苷酸的稳态水平在闭塞时间（3小时和24小时）方面存在显著的微小波动，但在比较对照半球与缺血半球时（3小时除外）则无波动。变化仅发生在出现缺血神经症状的动物中。闭塞后24小时，当在四个脑区的匀浆中测定时，低Km形式的环磷酸腺苷磷酸二酯酶的比活性升高，尤其是在缺血侧。另外，该酶在存在或不存在钙调蛋白的情况下的高Km形式没有变化。直到24小时过去，组织匀浆中的鸟苷酸环化酶活性才受到缺血条件的影响，这一情况同样仅在有症状的沙鼠中出现。在海马体、纹状体和嗅结节的缺血半球中，该酶对血晶素 - 过氧化氢酶的敏感性降低。此外，海马体和纹状体缺血侧中叠氮化钠对血晶素 - 过氧化氢酶反应的进一步激活受到抑制。综合这些研究和之前的研究表明，环核苷酸稳态水平的波动在急性缺血期间较为显著，在长时间缺血期间程度较轻，这些波动与负责其合成和/或降解的酶的相关变化无关。
