Baby Santhosh M, Discala Joseph F, Gruber Ryan, Getsy Paulina M, Cheng Feixiong, Damron Derek S, Lewis Stephen J
Galleon Pharmaceuticals Inc, Horsham, PA, United states.
Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United states.
Front Pharmacol. 2021 Sep 22;12:749084. doi: 10.3389/fphar.2021.749084. eCollection 2021.
We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts the cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective of the present study was to determine whether Tempol is able to reverse the effects of morphine on arterial blood-gas (ABG) chemistry in freely-moving Sprague Dawley rats. The intravenous injection of morphine (10 mg/kg) elicited substantial decreases in pH, pO and sO that were accompanied by substantial increases in pCO and Alveolar-arterial gradient, which results in diminished gas-exchange within the lungs. Intravenous injection of a 60 mg/kg dose of Tempol 15 min after the injection of morphine caused minor improvements in pO and pCO but not in other ABG parameters. In contrast, the 100 mg/kg dose of Tempol caused an immediate and sustained reversal of the negative effects of morphine on arterial blood pH, pCO, pO, sO and Alveolar-arterial gradient. In other rats, we used pulse oximetry to determine that the 100 mg/kg dose of Tempol, but not the 60 mg/kg dose elicited a rapid and sustained reversal of the negative effects of morphine (10 mg/kg, IV) on tissue O saturation (SpO). The injection of morphine caused a relatively minor fall in mean arterial blood pressure that was somewhat exacerbated by Tempol. These findings demonstrate that Tempol can reverse the negative effects of morphine on ABG chemistry in freely-moving rats paving the way of structure-activity and mechanisms of action studies with the host of Tempol analogues that are commercially available.
我们曾报道，在氟烷麻醉的大鼠中，用临床批准的超氧化物歧化酶模拟物Tempol（4-羟基-2,2,6,6-四甲基哌啶-N-氧基）进行预处理，可减弱随后注射芬太尼引起的心肺抑制反应。本研究的目的是确定Tempol是否能够逆转吗啡对自由活动的Sprague Dawley大鼠动脉血气（ABG）化学指标的影响。静脉注射吗啡（10mg/kg）导致pH、pO₂和sO₂显著降低，同时pCO₂和肺泡-动脉氧分压差大幅升高，这导致肺内气体交换减少。在注射吗啡15分钟后静脉注射60mg/kg剂量的Tempol，可使pO₂和pCO₂略有改善，但对其他ABG参数无影响。相比之下，100mg/kg剂量的Tempol可立即并持续逆转吗啡对动脉血pH、pCO₂、pO₂、sO₂和肺泡-动脉氧分压差的负面影响。在其他大鼠中，我们使用脉搏血氧饱和度测定法确定，100mg/kg剂量的Tempol而非60mg/kg剂量可迅速并持续逆转吗啡（10mg/kg，静脉注射）对组织氧饱和度（SpO₂）的负面影响。注射吗啡导致平均动脉血压相对轻微下降，Tempol对此有一定程度的加剧作用。这些发现表明，Tempol可逆转吗啡对自由活动大鼠ABG化学指标的负面影响，为对大量市售Tempol类似物进行构效关系和作用机制研究铺平了道路。
