Intracellular regulation and anesthetic modification regarding the augmentation of vascular contraction in diabetic condition

本研究旨在探讨糖尿病大鼠血管收缩增强的机制，以及七氟醚和异氟醚对各种蛋白激酶表达或细胞内信号通路的影响。1）与非糖尿病组相比，糖尿病组血管紧张素II诱导的离体大鼠去内皮主动脉收缩增强。七氟醚对血管紧张素II诱导的蛋白激酶C磷酸化有浓度依赖性的抑制作用，而异氟醚对血管紧张素II诱导的蛋白激酶C磷酸化无抑制作用。这一结果表明，七氟醚可抑制血管收缩通路的钙敏感性。3）血管紧张素H和苯肾上腺素可短暂刺激MLC、CPI-17、MYPT 1/Thr 853和/Thr 696的磷酸化。4）挥发性麻醉剂，七氟醚和异氟醚，以浓度依赖方式抑制血管紧张素II和苯丙氨酸刺激的MLC磷酸化。七氟烷可减弱血管加压素诱导的血管平滑肌张力，这与Rho激酶磷酸化有关。6）活性氧自由基通过使可溶性鸟苷酸环化酶（sGC）活性脱敏而影响NO-可溶性鸟苷酸环化酶（sGC）-cGMP通路，七氟烷暴露可加重sGC活性，这些结果表明，包括七氟醚和异氟醚在内的挥发性麻醉药通过不同的机制组合改变血管平滑肌张力的能力，包括血管收缩途径如蛋白激酶磷酸化和钙致敏，或舒张途径如NO-可溶性鸟苷酸环化酶（sGC）-cGMP途径，其也受糖尿病状况的影响。

This study was to investigate both the mechanism of enhanced vascular contractility in diabetes mellitus and the effects of volatile anesthetics including sevoflurane and isoflurane on the expression of various protein kinase or the intracellular signal pathway.1) The contraction of isolated rat aorta without endothelium induced by angiotensin II was enhanced in diabetic group compared with non-diabetic group. Sevoflurane inhibited the mnsrle tension in concentration-dependent manner, but isoflurane did not.2) Sevoflurane attenuated angiotensin II-induced phosphorylation of protein kinase C, which was examined by Western blotting, but not intracellular calcium concentration. This result suggests that sevoflurane would inhibit calcium sensitization of vascular contraction pathway.3) Angiotensin H and phenylephrine transiently stimulated the phosphorylation of MLC, CPI-17, MYPT1/Thr853, and /Thr696.4) Volatile anesthetics, both sevoflurane and isoflurane, inhibited the phosphorylation of MLC stimulated by angiotensin II and phenylephrine in concentration-dependent manner.5) Sevoflurane attenuated vascular smooth muscle tension induced by vasopressin, which was associated with Rho kinase phosphorylation.6) Reactive oxygen radicals affected the NO-soluble guanylate cyclase (sGC) -cGMP pathway by the desensitization of sGC activity, which was exaggerated by sevoflurane exposure, particularly in hyperoxic condition.These results suggested that that the ability of volatile anesthetics including sevoflurane and isoflurane to alter the vascular smooth muscle tension through different combination of mechanisms, including the vasclular contraction pathway such as protein kinase phospholyration and calcium sensitization, or the relaxation pathway such as NO-soluble guanylate cyclase (sGC) -cGMP pathway, which was also affected by diabetic condition.