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

本研究旨在探讨糖尿病患者血管收缩能力增强的机制，以及七氟醚和异氟醚等挥发性麻醉剂对多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诱导的无内皮大鼠离体主动脉收缩增强。七氟醚对微张力的抑制呈浓度依赖性，而异氟醚对微张力无抑制作用。2)七氟醚可减弱血管紧张素ii诱导的蛋白激酶C的磷酸化，但对细胞内钙浓度无影响。提示七氟醚可抑制血管收缩途径的钙致敏。3)血管紧张素H和苯肾上腺素可瞬时刺激MLC、CPI-17、MYPT1/Thr853和/Thr696.4的磷酸化。七氟醚和异氟醚挥发性麻醉剂均可抑制血管紧张素II和苯肾上腺素刺激的MLC磷酸化，且呈浓度依赖性。5)七氟醚可减弱抗利尿激素诱导的血管平滑肌张力，这种张力与Rho激酶磷酸化有关。6)活性氧自由基通过使sGC活性脱敏而影响no -可溶性鸟苷酸环化酶(sGC) -cGMP通路，七氟醚暴露使sGC活性脱敏，特别是在高氧条件下。这些结果提示，七氟醚和异氟醚等挥发性麻醉剂通过不同的机制组合改变血管平滑肌张力的能力，包括蛋白激酶磷酸化和钙致敏等血管收缩途径，或no -可溶性鸟苷酸环化酶(sGC) -cGMP等松弛途径，这些途径也受到糖尿病的影响。

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.