Wang Yan, Zhou Huixuan, Wu Bin, Zhou Quanhong, Cui Derong, Wang Li
Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
J Cardiovasc Pharmacol. 2015 Sep;66(3):276-84. doi: 10.1097/FJC.0000000000000275.
Protein kinase C (PKC) isoforms improve endothelial nitric oxide synthase activity and contractile Ca sensitivity in blood vessels. These actions may have opposite effects on propofol-induced vasodilation. This study examines the hypothesis that propofol induces relaxation by enhancing the PKC-mediated nitric oxide synthesis in endothelium and/or inhibiting the PKC-regulated Ca sensitivity in vascular smooth muscle (VSM). Propofol (1-100 μM) induced greater relaxation in endothelium-intact rings compared with denuded rings, and this effect was antagonized by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). In contrast, treatment with the general PKC inhibitor GF-109203X augmented both the endothelium-dependent and endothelium-independent relaxation induced by propofol, and this enhancement was more profound in the intact rings at lower propofol concentrations. The enhancement was unaffected by L-NAME. Interestingly, calphostin C (an inhibitor of conventional and novel PKCs) and Gö-6976 (an inhibitor of conventional PKCs) had similar effects in augmenting propofol-induced relaxation in endothelium-denuded rings. Downregulation of novel isoforms not only reduced the norepinephrine-elicited contraction but also decreased the magnitude of propofol-induced relaxation. In vascular smooth muscle cells, propofol prevented norepinephrine-elicited phosphorylation of myosin light chain. Propofol can increase the PKC-mediated availability of nitric oxide but inhibit the novel PKC-regulated Ca-sensitization, which provides a novel explanation for the mechanism of propofol-induced vasodilation.
蛋白激酶C（PKC）亚型可改善血管内皮一氧化氮合酶活性并提高血管收缩时的钙敏感性。这些作用可能对丙泊酚诱导的血管舒张产生相反影响。本研究检验了以下假说：丙泊酚通过增强内皮细胞中PKC介导的一氧化氮合成和/或抑制血管平滑肌（VSM）中PKC调节的钙敏感性来诱导血管舒张。与去内皮环相比，丙泊酚（1 - 100 μM）在内皮完整的血管环中诱导出更大程度的舒张，且一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）可拮抗这一效应。相反，用通用PKC抑制剂GF-109203X处理可增强丙泊酚诱导的内皮依赖性和非内皮依赖性舒张，且在较低丙泊酚浓度下，完整血管环中的这种增强作用更显著。这种增强作用不受L-NAME影响。有趣的是，钙泊司汀C（传统和新型PKC的抑制剂）和Gö-6976（传统PKC的抑制剂）在增强去内皮血管环中丙泊酚诱导的舒张方面具有相似作用。新型亚型的下调不仅降低了去甲肾上腺素引起的收缩，还减小了丙泊酚诱导的舒张幅度。在血管平滑肌细胞中，丙泊酚可阻止去甲肾上腺素引起的肌球蛋白轻链磷酸化。丙泊酚可增加PKC介导的一氧化氮生成，但抑制新型PKC调节的钙敏化，这为丙泊酚诱导血管舒张的机制提供了新的解释。
