Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Biomed Pharmacother. 2022 Feb;146:112571. doi: 10.1016/j.biopha.2021.112571. Epub 2021 Dec 22.
There is an urgent need to understand the intracellular mechanisms by which synthetic opioids, such as fentanyl, depress breathing. We used L-NAME (N-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor, to provide evidence for a role of nitric oxide (NO) and nitrosyl factors, including S-nitrosothiols, in fentanyl-induced suppression of breathing in rats. We measured breathing parameters using unrestrained plethysmography to record the changes produced by bolus administration of fentanyl (25 μg/kg, IV) in male Sprague Dawley rats that were pretreated with vehicle (saline), L-NAME (50 μmol/kg, IV) or the inactive D-isomer, D-NAME (50 μmol/kg, IV), 15 min previously. L-NAME produced a series of ventilatory changes that included (i) sustained elevations in breathing frequency, due to the reductions in the durations of inspiration and expiration, (ii) sustained elevations in minute ventilation, accompanied by minimal changes in tidal volume, and (iii) increases in inspiratory drive and expiratory drive, and peak inspiratory flow and peak expiratory flow. Subsequent administration of fentanyl in rats pretreated with vehicle produced negative effects on breathing, including decreases in frequency, tidal volume and therefore minute ventilation. Fentanyl elicited markedly different responses in rats that were pretreated with L-NAME, and conclusively, the negative effects of fentanyl were augmented by the NOS inhibitor. D-NAME did not alter ventilatory parameters or modulate the effects of fentanyl on breathing. Our study fully characterized the effects of L-NAME on ventilation in rats and is the first to suggest a potential role of nitrosyl factors in the ventilatory responses to fentanyl. Our data shows that nitrosyl factors reduce the expression of fentanyl-induced changes in ventilation.
目前迫切需要了解合成阿片类药物（如芬太尼）抑制呼吸的细胞内机制。我们使用 L-NAME（N-硝基-L-精氨酸甲酯），一种一氧化氮合酶（NOS）抑制剂，为一氧化氮（NO）和亚硝酰基因子（包括 S-亚硝基硫醇）在芬太尼诱导的大鼠呼吸抑制中的作用提供证据。我们使用无约束体积描记法测量呼吸参数，以记录预先给予载体（生理盐水）、L-NAME（50 μmol/kg，IV）或无活性 D-异构体 D-NAME（50 μmol/kg，IV）15 分钟后，静脉注射芬太尼（25μg/kg）引起的呼吸变化。L-NAME 产生了一系列通气变化，包括（i）呼吸频率持续升高，这是由于吸气和呼气持续时间缩短所致，（ii）分钟通气量持续升高，潮气量变化最小，以及（iii）吸气驱动力和呼气驱动力以及吸气峰流速和呼气峰流速增加。在预先给予载体的大鼠中，随后给予芬太尼会对呼吸产生负面影响，包括频率、潮气量和因此分钟通气量降低。芬太尼在预先给予 L-NAME 的大鼠中引起明显不同的反应，并且结论是，NOS 抑制剂增强了芬太尼的负面效应。D-NAME 不会改变通气参数或调节芬太尼对呼吸的影响。我们的研究充分描述了 L-NAME 对大鼠通气的影响，并且首次提出亚硝酰基因子在芬太尼通气反应中的潜在作用。我们的数据表明，亚硝酰基因子减少了芬太尼诱导的通气变化的表达。
