20-羟基二十碳四烯酸通过蛋白激酶Cα介导的钾钙通道抑制作用增强犬基底动脉的牵张诱导收缩。

20-Hydroxyeicosatetraenoic acid potentiates stretch-induced contraction of canine basilar artery via PKC alpha-mediated inhibition of KCa channel.

Obara Kazuo, Koide Masayo, Nakayama Koichi

Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.

Br J Pharmacol. 2002 Dec;137(8):1362-70. doi: 10.1038/sj.bjp.0704960.

Abstract

The present study was undertaken to elucidate whether PKCalpha plays a role in the mechanism of the stretch-induced contraction potentiated by 20-hydroxyeicosatetraenoic acid (20-HETE). The effects of 20-HETE on the canine basilar artery were compared with those of iberiotoxin, a blocker of large conductance Ca(2+)-activated K(+) channels (K(Ca) channels), as this blocker was shown earlier to sensitize these arteries to mechanical stretch. 2. Slow stretch at rates of 0.1 to 3 mm s(-1) did not produce any contraction in normal physiological solution. 3. In the presence of 20-HETE, the slow stretch could produce contraction, which was inhibited by nicardipine, a 1,4-dihydropyridine Ca(2+) channel blocker, and gadolinium, a blocker of stretch-activated cation channels. 4. 20-HETE inhibited whole-cell K(+) current and depolarized the membrane by approximately 10 mV. These effects of 20-HETE were similar to those of iberiotoxin. 5. Calphostin C, an inhibitor of protein kinase C (PKC), inhibited the action of 20-HETE, but not that of iberiotoxin. 6. In response to 20-HETE PKCalpha isoform was translocated from the cytosol to the membrane fraction, which translocation was inhibited by calphostin C. 7. These results suggest that 20-HETE induced sensitization of the canine basilar artery to stretch was caused by PKCalpha-mediated inhibition of K(Ca) channel activity.

摘要

本研究旨在阐明蛋白激酶Cα（PKCalpha）是否在20-羟基二十碳四烯酸（20-HETE）增强的牵张诱导收缩机制中发挥作用。将20-HETE对犬基底动脉的作用与大电导钙激活钾通道（K（Ca）通道）阻滞剂iberiotoxin的作用进行比较，因为先前已表明该阻滞剂可使这些动脉对机械牵张敏感。2. 在正常生理溶液中，以0.1至3 mm s(-1)的速率缓慢牵张不会产生任何收缩。3. 在存在20-HETE的情况下，缓慢牵张可产生收缩，该收缩被1,4-二氢吡啶钙通道阻滞剂尼卡地平以及牵张激活阳离子通道阻滞剂钆抑制。4. 20-HETE抑制全细胞钾电流并使膜去极化约10 mV。20-HETE的这些作用与iberiotoxin的作用相似。5. 蛋白激酶C（PKC）抑制剂Calphostin C抑制20-HETE的作用，但不抑制iberiotoxin的作用。6. 响应20-HETE，PKCalpha亚型从胞质溶胶转位至膜部分，该转位被Calphostin C抑制。7. 这些结果表明，20-HETE诱导的犬基底动脉对牵张的敏感性增加是由PKCalpha介导的K（Ca）通道活性抑制引起的。