Kulier A H, Turner L A, Vodanovic S, Contney S, Lathrop D A, Bosnjak Z J
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Anesthesiology. 2000 Jun;92(6):1713-21. doi: 10.1097/00000542-200006000-00031.
Halothane more so than isoflurane potentiates an alpha1-adrenoceptor (alpha1-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. This adverse drug interaction was further evaluated by examining conduction responses to epinephrine in combination with thiopental and propofol, which "sensitize" or reduce the dose of epinephrine required to induce arrhythmias in the heart, and with etomidate, which does not, and responses to epinephrine with verapamil, lidocaine, and l-palmitoyl carnitine, a potential ischemic metabolite.
Action potentials and conduction times were measured in vitro using two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 microm epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (Vmax) and the electrotonic spread of intracellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular coupling) membrane properties in the transient depression of conduction velocity.
Lidocaine (20 microm) and octanol (0.2 mm) potentiated alpha1-AR-induced conduction depression like halothane (0.4 mm), with maximum depression at 3-5 min of agonist exposure, no decrease of Vmax, and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 microm), propofol (50 microm), and verapamil (2 microm) similarly potentiated epinephrine responses, whereas etomidate (10 microm) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 microm) l-palmitoyl carnitine (-18%) was significantly greater than that resulting from epinephrine alone (-6%; 0.05 </= P </= 0.10). Current injection experiments were consistent with marked transient inhibition of cell-to-cell coupling correlating with alpha1-AR conduction depression in fibers exposed to octanol.
Anesthetic "sensitization" to the arrhythmogenic effects of catecholamines may be a special case of a more general phenomenon by which not only some anesthetics and antiarrhythmic drugs but also possible ischemic fatty acid metabolites potentiate conduction depression due to acute alpha1-AR-mediated cell-to-cell uncoupling.
与异氟烷相比，氟烷更易增强α1肾上腺素能受体（α1-AR）介导的肾上腺素作用，该作用会异常减慢浦肯野纤维的传导，并可能促进折返性心律失常。通过检测肾上腺素与硫喷妥钠和丙泊酚联合使用时的传导反应，进一步评估了这种不良药物相互作用。硫喷妥钠和丙泊酚会“致敏”或降低心脏诱发心律失常所需的肾上腺素剂量，而依托咪酯则不会。此外，还检测了肾上腺素与维拉帕米、利多卡因和l-棕榈酰肉碱（一种潜在的缺血代谢产物）联合使用时的反应。
使用两个微电极在体外测量犬浦肯野纤维组的动作电位和传导时间，刺激频率为每分钟150次脉冲。在单独暴露于5微摩尔肾上腺素（或去氧肾上腺素）或与测试药物联合使用后，每分钟评估一次传导情况。在用辛醇暴露于肾上腺素期间，测量0期去极化速率（Vmax）和细胞内电流的电紧张性扩布变化，以评估抑制主动和被动（细胞间耦联）膜特性在传导速度短暂降低中的作用。
利多卡因（20微摩尔）和辛醇（0.2毫摩尔）与氟烷（0.4毫摩尔）一样，增强了α1-AR诱导的传导抑制，在激动剂暴露3 - 5分钟时抑制作用最大，Vmax无降低，在快速（250次/分钟与150次/分钟）刺激频率下增强作用较小。硫喷妥钠（95微摩尔）、丙泊酚（50微摩尔）和维拉帕米（2微摩尔）同样增强了肾上腺素反应，而依托咪酯（10微摩尔）则没有。在各组之间，肾上腺素在（10微摩尔）l-棕榈酰肉碱存在下诱导的速度降低（-18%）明显大于单独使用肾上腺素时的降低（-6%；0.05≤P≤0.10）。电流注入实验与在暴露于辛醇的纤维中与α1-AR传导抑制相关的细胞间耦联的明显短暂抑制一致。
麻醉药对儿茶酚胺致心律失常作用的“致敏”可能是一种更普遍现象的特殊情况，即不仅一些麻醉药和抗心律失常药物，而且可能的缺血性脂肪酸代谢产物都会因急性α1-AR介导的细胞间解耦联而增强传导抑制。
