Akata T, Nakashima M, Kodama K, Boyle W A, Takahashi S
Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Anesthesiology. 1995 Jan;82(1):188-204. doi: 10.1097/00000542-199501000-00024.
Vascular endothelium plays an important role in the regulation of vascular tone. Volatile anesthetics have been shown to attenuate endothelium-mediated relaxation in conductance arteries, such as aorta. However, significant differences in volatile anesthetic pharmacology between these large vessels and the small vessels that regulate systemic vascular resistance and blood flow have been documented, yet little is known about volatile anesthetic action on endothelial function in resistance arteries. Furthermore, endothelium-dependent relaxation mediated by factors other than endothelium-derived relaxing factor (EDRF) has recently been recognized, and there is no information available regarding volatile anesthetic action on non-EDRF-mediated endothelium-dependent relaxation.
Employing isometric tension recording and microelectrode methods, the authors first characterized the endothelium-dependent relaxing and hyperpolarizing actions of acetylcholine (ACh) in rabbit small mesenteric arteries, and tested the sensitivities of these actions to EDRF pathway inhibitors and K+ channel blockers. They then examined the effects of the volatile anesthetics isoflurane, enflurane, and sevoflurane on ACh-induced endothelium-dependent relaxation that was sensitive to EDRF inhibitors and that which was resistant to the EDRF inhibitors but sensitive to blockers of ACh-induced hyperpolarization. The effects of the volatile anesthetics on endothelium-independent sodium nitroprusside (SNP)-induced relaxation were also studied.
Acetylcholine concentration-dependently caused both endothelium-dependent relaxation and hyperpolarization of vascular smooth muscle. The relaxation elicited by low concentrations of ACh (< or = 0.1 microM) was almost completely abolished by the EDRF inhibitors NG-nitro-L-arginine (LNNA), oxyhemoglobin (HbO2), and methylene blue (MB). The relaxation elicited by higher concentrations of ACh (> or = 0.3 microM) was only attenuated by the EDRF inhibitors. The remaining relaxation, as well as the ACh-induced hyperpolarization that was also resistant to EDRF inhibitors, were both specifically blocked by tetraethylammonium (TEA > or = 10 mM). Sodium nitroprusside, a NO donor, produced dose-dependent relaxation, but not hyperpolarization, in the endothelium-denuded (E[-]) strips, and the relaxation was inhibited by MB and HbO2, but not TEA (> or = 10 mM). One MAC isoflurane, enflurane, and sevoflurane inhibited both ACh relaxation that was sensitive to the EDRF inhibitors and the ACh relaxation resistant to the EDRF inhibitors and sensitive to TEA, but not SNP relaxation (in the E[-] strips). An additional finding was that the anesthetics all significantly inhibited norepinephrine (NE) contractions in the presence and absence of the endothelium or after exposure to the EDRF inhibitors.
The results confirm that ACh has a hyperpolarizing action in rabbit small mesenteric resistance arteries that is independent of EDRF inhibitors but blocked by the K+ channel blocker TEA. The ACh relaxation in these resistance arteries thus appears to consist of distinct EDRF-mediated and hyperpolarization-mediated components. Isoflurane, enflurane, and sevoflurane inhibited both components of the ACh-induced relaxation in these small arteries, indicating a more global depression of endothelial function or ACh signaling in endothelial cells, rather than a specific effect on the EDRF pathway. All these anesthetics exerted vasodilating action in the presence of NE, the primary neurotransmitter of the sympathetic nervous system, which plays a major role in maintaining vasomotor tone in vivo. This strongly indicates that the vasodilating action of these anesthetics probably dominates over their inhibitory action on the EDRF pathway and, presumably, contributes to their known hypotensive effects in vivo. Finally, the vasodilating action of these anesthetics is, at least in part, independent from endothelium.
血管内皮在血管张力调节中起重要作用。挥发性麻醉药已被证明可减弱诸如主动脉等传导动脉中内皮介导的舒张作用。然而，已证明这些大血管与调节全身血管阻力和血流的小血管之间在挥发性麻醉药药理学方面存在显著差异，而关于挥发性麻醉药对阻力动脉内皮功能的作用却知之甚少。此外，最近已认识到除内皮源性舒张因子（EDRF）以外的其他因素介导的内皮依赖性舒张，且尚无关于挥发性麻醉药对非EDRF介导的内皮依赖性舒张作用的信息。
作者采用等长张力记录和微电极方法，首先对乙酰胆碱（ACh）在兔小肠系膜动脉中的内皮依赖性舒张和超极化作用进行了表征，并测试了这些作用对EDRF途径抑制剂和钾通道阻滞剂的敏感性。然后，他们研究了挥发性麻醉药异氟烷、恩氟烷和七氟烷对ACh诱导的内皮依赖性舒张的影响，该舒张对EDRF抑制剂敏感，以及对EDRF抑制剂耐药但对ACh诱导的超极化阻滞剂敏感的情况。还研究了挥发性麻醉药对非内皮依赖性硝普钠（SNP）诱导的舒张的影响。
乙酰胆碱浓度依赖性地引起血管平滑肌的内皮依赖性舒张和超极化。低浓度ACh（≤0.1微摩尔/升）引起的舒张几乎完全被EDRF抑制剂NG-硝基-L-精氨酸（LNNA）、氧合血红蛋白（HbO2）和亚甲蓝（MB）消除。高浓度ACh（≥0.3微摩尔/升）引起的舒张仅被EDRF抑制剂减弱。其余的舒张以及对EDRF抑制剂也耐药的ACh诱导的超极化均被四乙铵（TEA≥10毫摩尔/升）特异性阻断。NO供体硝普钠在去内皮（E[-]）条带中产生剂量依赖性舒张，但不产生超极化，且该舒张被MB和HbO2抑制，但不被TEA（≥10毫摩尔/升）抑制。一个最低肺泡有效浓度的异氟烷、恩氟烷和七氟烷抑制了对EDRF抑制剂敏感的ACh舒张以及对EDRF抑制剂耐药且对TEA敏感的ACh舒张，但不抑制SNP舒张（在E[-]条带中）。另一个发现是，无论有无内皮或在暴露于EDRF抑制剂后，这些麻醉药均显著抑制去甲肾上腺素（NE）收缩。
结果证实ACh在兔小肠系膜阻力动脉中具有超极化作用；该作用不依赖于EDRF抑制剂，但被钾通道阻滞剂TEA阻断。因此，这些阻力动脉中的ACh舒张似乎由不同的EDRF介导和超极化介导成分组成。异氟烷、恩氟烷和七氟烷抑制了这些小动脉中ACh诱导舒张的两个成分，表明对内皮功能或内皮细胞中ACh信号传导有更全面的抑制，而不是对EDRF途径有特异性作用。所有这些麻醉药在交感神经系统的主要神经递质NE存在时均发挥血管舒张作用，NE在体内维持血管运动张力中起主要作用。这强烈表明这些麻醉药的血管舒张作用可能超过其对EDRF途径的抑制作用，并且大概有助于其已知的体内降压作用。最后，这些麻醉药的血管舒张作用至少部分独立于内皮。
