Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
J Pharmacol Sci. 2012;119(3):271-81. doi: 10.1254/jphs.12024fp. Epub 2012 Jun 29.
Excessive stretching of the vascular wall in accordance with pulmonary arterial hypertension (PAH) induces a variety of pathogenic cellular events in the pulmonary arteries. We previously reported that indoxam, a selective inhibitor for secretory phospholipase A(2) (sPLA(2)), blocked the stretch-induced contraction of rabbit pulmonary arteries by inhibition of untransformed prostaglandin H(2) (PGH(2)) production. The present study was undertaken to investigate involvement of sPLA(2) and untransformed PGH(2) in the enhanced contractility of pulmonary arteries of experimental PAH in rats. Among all the known isoforms of sPLA(2), sPLA(2)-X transcript was most significantly augmented in the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PHR). The pulmonary arteries of MCT-PHR frequently showed two types of spontaneous contraction in response to stretch; 27% showed rhythmic contraction, which was sensitive to indoxam and SC-560 (selective COX-1 inhibitor), but less sensitive to NS-398 (selective COX-2 inhibitor); and 47% showed sustained incremental tension (tonic contraction), which was insensitive to indoxam and SC-560, but sensitive to NS-398 and was attenuated to 45% of the control. Only the rhythmically contracting pulmonary arteries of MCT-PHR produced a substantial amount of untransformed PGH(2), which was abolished by indoxam. These results suggest that sPLA(2)-mediated PGH(2) synthesis plays an important role in the rhythmic contraction of pulmonary arteries of MCT-PHR.
根据肺动脉高压 (PAH)，血管壁的过度拉伸会在肺血管中引起多种致病的细胞事件。我们之前曾报道过，选择性分泌型磷脂酶 A2（sPLA2）抑制剂吲哚美辛通过抑制未转化的前列腺素 H2（PGH2）的产生，阻断了兔肺血管拉伸诱导的收缩。本研究旨在探讨 sPLA2 和未转化的 PGH2 在实验性 PAH 大鼠肺血管收缩性增强中的作用。在所有已知的 sPLA2 同工型中，sPLA2-X 转录本在 MCT-PHR 大鼠肺血管中增加最为显著。MCT-PHR 大鼠的肺血管经常对拉伸表现出两种类型的自发性收缩；27%表现出节律性收缩，对吲哚美辛和 SC-560（选择性 COX-1 抑制剂）敏感，但对 NS-398（选择性 COX-2 抑制剂）不敏感；47%表现出持续递增张力（紧张性收缩），对吲哚美辛和 SC-560 不敏感，但对 NS-398 敏感，且收缩幅度为对照组的 45%。只有 MCT-PHR 的节律性收缩肺血管产生大量的未转化的 PGH2，吲哚美辛可以消除其产生。这些结果表明，sPLA2 介导的 PGH2 合成在 MCT-PHR 大鼠肺血管的节律性收缩中发挥重要作用。
