Smeda J S, King S
Division of Basic Medical Sciences, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
Stroke. 1999 Mar;30(3):656-61. doi: 10.1161/01.str.30.3.656.
Cerebrovascular pressure-dependent constriction may involve the smooth muscle production of diacylglycerol, which could facilitate constriction by activating protein kinase C (PKC). A dysfunctional PKC system could promote the loss of pressure-dependent constriction. We attempted to determine whether the alterations in pressure-dependent constriction in the middle cerebral arteries (MCAs) observed in relation to stroke development in Wistar-Kyoto stroke-prone spontaneously hypertensive rats (SHRsp) were associated with defects in the ability of the arteries to constrict in response to PKC activation.
MCAs were sampled from SHRsp before and after stroke development and in stroke-resistant Wistar-Kyoto spontaneously hypertensive rats. A pressure myograph was used to test the ability of the arteries to constrict in response to a 100 mm Hg pressure step and subsequently to contract in response to phorbol 12,13-dibutyrate in the presence of nifedipine (3 micromol/L).
Pressure-dependent constriction and constriction in response to phorbol dibutyrate in the MCAs were inhibited by PKC inhibitors (staurosporine [40 nmol/L], chelerythrine [12 micromol/L], bisindolylmaleimide [5 micromol/L]), declined with age before stroke development in SHRsp, and were absent after stroke. There was a significant relationship between pressure- and phorbol dibutyrate-induced constriction (r=0.815, P<0. 05).
Phorbol esters interact with the same activation site as diacylglycerol to stimulate PKC. An inability to constrict in response to phorbol dibutyrate may reflect unresponsiveness to diacylglycerol and may contribute to the loss of pressure-dependent constriction associated with stroke in the MCAs of SHRsp. The loss of this autoregulatory function before stroke could increase the risk of cerebral hemorrhage.
脑血管压力依赖性收缩可能涉及二酰甘油的平滑肌生成，其可通过激活蛋白激酶C（PKC）促进收缩。功能失调的PKC系统可能会导致压力依赖性收缩丧失。我们试图确定，在易患中风的Wistar - Kyoto自发性高血压大鼠（SHRsp）中，观察到的与中风发展相关的大脑中动脉（MCA）压力依赖性收缩变化，是否与动脉对PKC激活的收缩能力缺陷有关。
在中风发展前后从SHRsp以及抗中风的Wistar - Kyoto自发性高血压大鼠中采集MCA。使用压力肌动描记法测试动脉对100 mmHg压力阶跃的收缩能力，随后在硝苯地平（3 μmol/L）存在的情况下对佛波醇12,13 - 二丁酸酯的收缩反应。
PKC抑制剂（星形孢菌素[40 nmol/L]、白屈菜红碱[12 μmol/L]、双吲哚马来酰胺[5 μmol/L]）可抑制MCA中的压力依赖性收缩以及对佛波醇二丁酸酯的收缩反应，在SHRsp中风发展前随年龄下降，中风后则消失。压力和佛波醇二丁酸酯诱导的收缩之间存在显著相关性（r = 0.815，P < 0.05）。
佛波酯与二酰甘油作用于相同的激活位点以刺激PKC。对佛波醇二丁酸酯无收缩反应可能反映了对二酰甘油无反应，并可能导致SHRsp的MCA中与中风相关的压力依赖性收缩丧失。中风前这种自动调节功能的丧失可能会增加脑出血的风险。
