Kessler P, Lischke V, Hecker M
Center of Anesthesiology and Resuscitation, Johann Wolfgang Goethe University Clinic, Frankfurt am Main, Germany.
Anesthesiology. 1996 Jun;84(6):1485-8. doi: 10.1097/00000542-199606000-00025.
Endothelium-derived hyperpolarizing factor is thought to be a cytochrome P450-derived arachidonic acid metabolite that hyperpolarizes vascular smooth muscle cells by opening Ca(2+)-activated K+ channels (K+Ca channels). In the rabbit carotid artery both volatile and intravenous anesthetics inhibit the acetylcholine-stimulated release of endothelium-derived hyperpolarizing factor. Because the release of this factor may help to maintain vascular tone in humans under conditions of a failing nitric oxide synthesis, e.g., in atherosclerosis, the effects of two intravenous anesthetics, thiopental and etomidate, on the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine were investigated in human isolated renal artery segments.
The segments were suspended in Krebs-Henseleit solution (37 degrees C) containing the cyclooxygenase inhibitor diclofenac (1 microM) and preconstricted with norepinephrine (6 microM). Relaxations caused by acetylcholine (1 microM) were compared in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (0.1 mM) in control segments and in segments exposed to etomidate or thiopental (0.03-0.3 mM). In addition, the effects of the two anesthetics on the relaxant response to the nitric oxide donors glyceryl trinitrate (3 microM) and sodium nitroprusside (0.1 microM) were examined.
The relaxant response to acetylcholine, which was resistant to both nitric oxide synthase and cyclooxygenase blockade, was markedly reduced by the K+Ca channel antagonist tetrabutyl ammonium (3 mM) and the cytochrome P450 inhibitor clotrimazole (30 microM). Both etomidate and thiopental, at a concentration of 0.3 mM, selectively attenuated the relaxant response to acetylcholine in N(G)-nitro-L-arginine-treated segments, but did not affect relaxations elicited by glyceryl trinitrate or sodium nitroprusside.
Etomidate and thiopental inhibit the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine in the human renal artery, an effect that appears to be attributable to the cytochrome P450-inhibiting properties of these anesthetics.
内皮衍生超极化因子被认为是一种细胞色素P450衍生的花生四烯酸代谢产物，它通过打开钙激活钾通道（K⁺Ca通道）使血管平滑肌细胞超极化。在兔颈动脉中，挥发性和静脉麻醉药均抑制乙酰胆碱刺激的内皮衍生超极化因子的释放。由于在一氧化氮合成功能衰竭的情况下，例如动脉粥样硬化时，该因子的释放可能有助于维持人体血管张力，因此研究了两种静脉麻醉药硫喷妥钠和依托咪酯对人离体肾动脉段中内皮衍生超极化因子介导的对乙酰胆碱的舒张反应的影响。
将动脉段悬挂于含环氧合酶抑制剂双氯芬酸（1微摩尔）的 Krebs-Henseleit 溶液（37℃）中，并用去甲肾上腺素（6微摩尔）预收缩。在对照段以及暴露于依托咪酯或硫喷妥钠（0.03 - 0.3毫摩尔）的段中，比较在存在和不存在一氧化氮合酶抑制剂N⁰-硝基-L-精氨酸（0.1毫摩尔）的情况下乙酰胆碱（1微摩尔）引起的舒张作用。此外，还研究了这两种麻醉药对一氧化氮供体硝酸甘油（3微摩尔）和硝普钠（0.1微摩尔）舒张反应的影响。
对乙酰胆碱的舒张反应，对一氧化氮合酶和环氧合酶阻断均有抗性，被钾钙通道拮抗剂四丁基铵（3毫摩尔）和细胞色素P450抑制剂克霉唑（30微摩尔）显著降低。在浓度为0.3毫摩尔时，依托咪酯和硫喷妥钠均选择性减弱了N⁰-硝基-L-精氨酸处理段中对乙酰胆碱的舒张反应，但不影响硝酸甘油或硝普钠引起的舒张。
依托咪酯和硫喷妥钠抑制人肾动脉中内皮衍生超极化因子介导的对乙酰胆碱的舒张反应，这种作用似乎归因于这些麻醉药的细胞色素P450抑制特性。
