University at Buffalo, 352 Kapoor Hall, Buffalo, NY 14214, USA.
Mol Pharmacol. 2012 Aug;82(2):226-35. doi: 10.1124/mol.112.078154. Epub 2012 May 4.
Overdose of γ-hydroxybutyrate (GHB) frequently causes respiratory depression, occasionally resulting in death; however, little is known about the dose-response relationship or effects of potential overdose treatment strategies on GHB-induced respiratory depression. In these studies, the parameters of respiratory rate, tidal volume, and minute volume were measured using whole-body plethysmography in rats administered GHB. Intravenous doses of 200, 600, and 1500 mg/kg were administered to assess the dose-dependent effects of GHB on respiration. To determine the receptors involved in GHB-induced respiratory depression, a specific GABA(B) receptor antagonist, (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), and a specific GABA(A) receptor antagonist, bicuculline, were administered before GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 min after GHB. The primary effect of GHB on respiration was a dose-dependent decrease in respiratory rate, accompanied by an increase in tidal volume, resulting in little change in minute volume. Pretreatment with 150 mg/kg SCH50911 completely prevented the decrease in respiratory rate, indicating agonism at GABA(B) receptors to be primarily responsible for GHB-induced respiratory depression. Administration of 50 mg/kg SCH50911 after GHB completely reversed the decrease in respiratory rate; lower doses had partial effects. Administration of the MCT inhibitor l-lactate increased GHB renal and total clearance, also improving respiratory rate. Administration of 5 mg/kg SCH50911 plus l-lactate further improved respiratory rate compared with the same dose of either agent alone, indicating that GABA(B) and MCT inhibitors, alone and in combination, represent potential treatment options for GHB-induced respiratory depression.
γ-羟基丁酸（GHB）过量经常导致呼吸抑制，偶尔导致死亡；然而，对于 GHB 诱导的呼吸抑制的剂量-反应关系或潜在过量治疗策略的影响知之甚少。在这些研究中，使用全身 plethysmography 在给予 GHB 的大鼠中测量呼吸频率、潮气量和分钟通气量等参数。给予 200、600 和 1500mg/kg 的静脉剂量以评估 GHB 对呼吸的剂量依赖性影响。为了确定 GHB 诱导的呼吸抑制涉及的受体，在给予 GHB 之前给予特定的 GABA(B)受体拮抗剂（2S）-（+）-5,5-二甲基-2-吗啉乙 酸（SCH50911）和特定的 GABA(A)受体拮抗剂荷包牡丹碱。通过在给予 GHB 后 5 分钟给予抑制剂来评估受体抑制和单羧酸转运蛋白（MCT）抑制的潜在治疗策略。GHB 对呼吸的主要影响是呼吸频率的剂量依赖性降低，同时潮气量增加，导致分钟通气量几乎没有变化。150mg/kgSCH50911 的预处理完全阻止了呼吸率的降低，表明 GABA(B)受体激动剂主要负责 GHB 诱导的呼吸抑制。给予 50mg/kgSCH50911 后，完全逆转了呼吸率的降低；较低剂量具有部分作用。MCT 抑制剂 l-乳酸盐的给予增加了 GHB 的肾脏和总清除率，也改善了呼吸率。给予 5mg/kgSCH50911 加 l-乳酸盐与单独给予相同剂量的任何一种药物相比，进一步改善了呼吸率，表明 GABA(B)和 MCT 抑制剂单独和联合使用，是治疗 GHB 诱导的呼吸抑制的潜在选择。
