Kanellopoulos A, Lenz G, Mühlbauer B
Department of Pediatrics, University of Marburg, Germany.
Anesthesiology. 1998 Mar;88(3):718-24. doi: 10.1097/00000542-199803000-00023.
S(+) ketamine, because of its higher anesthetic potency and lower risk of psychotomimetic reactions, has been suggested to be superior to presently available racemic ketamine. The racemate is a direct vasodilator in vivo, and thus the authors investigated the vasorelaxing effects of ketamine enantiomers on rat aorta.
Rat isolated aortic rings with and without endothelium were contracted with 3 x 10(-7) M norepinephrine. Then 10(-5) to 3 x 10(-3) M S(+), R(-), or racemic ketamine were added cumulatively. Vascular responses to ketamine were further studied in rings pretreated with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (NNLA), the adenosine triphosphate-sensitive K+ channel antagonist glibenclamide, and the L-type calcium channel blocking agent D888.
Ketamine enantiomers and the racemate produced concentration-dependent vasorelaxation. The relaxing effect of S(+) ketamine was significantly weaker compared with R(-) ketamine and the racemate reflected by the half-maximum effective concentration (EC50) values of 11.6 x 10(-4), 4.8 x 10(-4), and 6 x 10(-4) M, respectively. Removal of the endothelium and NNLA or glibenclamide pretreatment did not significantly alter the vasorelaxing effect of ketamine. In contrast, D888 pretreatment significantly shifted the concentration-effect curves of both S(+) and R(-) ketamine rightward (EC50 values of 18.9 x 10(-4) and 8.5 x 10(-4) M, respectively), whereas the difference between the isomers was not affected.
Vasorelaxation by ketamine enantiomers is quantitatively stereoselective: The effect of S(+)ketamine is significantly weaker compared with that of the racemate and R(-) ketamine. This stereoselective difference is not due to nitric oxide release, activation of adenosine triphosphate-sensitive potassium channels, or differential inhibition of L-type calcium channels.
S(+)氯胺酮因其较高的麻醉效能和较低的拟精神反应风险，被认为优于现有的消旋氯胺酮。消旋体在体内是一种直接的血管扩张剂，因此作者研究了氯胺酮对映体对大鼠主动脉的血管舒张作用。
用3×10(-7)M去甲肾上腺素使有内皮和无内皮的大鼠离体主动脉环收缩。然后累积加入10(-5)至3×10(-3)M的S(+)、R(-)或消旋氯胺酮。在用一氧化氮合酶抑制剂N(ω)-硝基-L-精氨酸(NNLA)、三磷酸腺苷敏感性钾通道拮抗剂格列本脲和L型钙通道阻滞剂D888预处理的血管环中进一步研究氯胺酮的血管反应。
氯胺酮对映体和消旋体产生浓度依赖性血管舒张。S(+)氯胺酮的舒张作用明显弱于R(-)氯胺酮和消旋体，半数有效浓度(EC50)值分别为11.6×10(-4)、4.8×10(-4)和6×10(-4)M。去除内皮以及NNLA或格列本脲预处理均未显著改变氯胺酮的血管舒张作用。相反，D888预处理使S(+)和R(-)氯胺酮的浓度-效应曲线均显著右移(EC50值分别为18.9×10(-4)和8.5×10(-4)M)，而异构体之间的差异未受影响。
氯胺酮对映体的血管舒张具有定量立体选择性：S(+)氯胺酮的作用明显弱于消旋体和R(-)氯胺酮。这种立体选择性差异不是由于一氧化氮释放、三磷酸腺苷敏感性钾通道激活或L型钙通道的差异抑制所致。
