Joseph Vincent, Uppari NagaPraveena, Kouchi Hayet, De Bruyn Celia, Boukari Ryma, Bairam Aida
Centre de recherche de l'institut de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Faculté de médicine, Université Laval, Québec, Québec, Canada.
Exp Physiol. 2018 Feb 1;103(2):276-290. doi: 10.1113/EP086716. Epub 2018 Jan 14.
What is the central question of this study? What are the contributions of allopregnanolone, the neuroactive metabolite of progesterone, and nuclear (nPR) and membrane (mPR) progesterone receptors to the respiratory effect of progesterone in newborn rats? What is the main finding and its importance? Acute progesterone injection increases the apnoea frequency, whereas finasteride (which blocks the conversion of progesterone to allopregnanolone) reduces apnoea frequency. An nPR agonist decreases apnoea frequency in males and an mPR agonist decreases apnoea frequency in males and females. Chronic injection of progesterone decreases the frequency of apnoea more efficiently in males than in females. We tested the hypothesis that the effects of progesterone on apnoea frequency in newborn rats are the result of a balance between its neuroactive metabolite, allopregnanolone (GABA receptor modulator), and progesterone receptors. We used male and female rats between 10 and 12 days of age and recorded respiratory and metabolic parameters (whole-body plethysmography), and assessed the frequency and duration of apnoeas in normoxia. We tested the effects of a single injection of progesterone (4 mg kg , i.p.), finasteride (10 mg kg , i.p.; a 5α-reductase antagonist, which blocks the conversion of progesterone to allopregnanolone), finasteride plus progesterone, or agonists of the nuclear or membrane progesterone receptors (R5020 or Org-od-02-0, 4 mg kg ). To test the hypothesis that chronic exposure to progesterone reduces the frequency of apnoeas, we used male and female rats treated daily with progesterone between postnatal days 3 and 12. The acute injection of progesterone reduced minute ventilation and metabolic rate and increased the frequency of apnoeas. Finasteride decreased the frequency of apnoeas, and finasteride plus progesterone did not increase apnoea frequency but decreased minute ventilation in female rats. Although R5020 decreased apnoea frequency only in males, Org-od-02-0 decreased apnoea frequency in males and females and decreased respiratory frequency in females. Chronic progesterone treatment reduced apnoea frequency more efficiently in males than in females, but in females (not in males) an acute injection of caffeine (the gold standard for the treatment of apnoea in preterm neonates) further reduced apnoea frequency. Apnoea frequency in newborn rats is, in part, determined by a sex-specific balance between allopregnanolone, GABA receptors and progesterone receptors.
本研究的核心问题是什么？孕酮的神经活性代谢产物别孕烯醇酮以及核孕酮受体（nPR）和膜孕酮受体（mPR）对新生大鼠孕酮呼吸效应的作用是什么？主要发现及其重要性是什么？急性注射孕酮会增加呼吸暂停频率，而非那雄胺（可阻断孕酮向别孕烯醇酮的转化）会降低呼吸暂停频率。一种nPR激动剂可降低雄性大鼠的呼吸暂停频率，一种mPR激动剂可降低雄性和雌性大鼠的呼吸暂停频率。慢性注射孕酮对雄性大鼠呼吸暂停频率的降低作用比雌性大鼠更有效。我们检验了这样一种假设，即孕酮对新生大鼠呼吸暂停频率的影响是其神经活性代谢产物别孕烯醇酮（一种GABA受体调节剂）和孕酮受体之间平衡的结果。我们使用了10至12日龄的雄性和雌性大鼠，记录呼吸和代谢参数（全身体积描记法），并评估常氧下呼吸暂停的频率和持续时间。我们测试了单次注射孕酮（4毫克/千克，腹腔注射）、非那雄胺（10毫克/千克，腹腔注射；一种5α - 还原酶拮抗剂，可阻断孕酮向别孕烯醇酮的转化）、非那雄胺加孕酮或核或膜孕酮受体激动剂（R5020或Org - od - 02 - 0，4毫克/千克）的效果。为了检验慢性暴露于孕酮会降低呼吸暂停频率这一假设，我们使用了在出生后第3天至第12天每天接受孕酮治疗的雄性和雌性大鼠。急性注射孕酮会降低分钟通气量和代谢率，并增加呼吸暂停频率。非那雄胺降低了呼吸暂停频率，非那雄胺加孕酮并未增加呼吸暂停频率，但降低了雌性大鼠的分钟通气量。虽然R5020仅降低了雄性大鼠的呼吸暂停频率，但Org - od - 02 - 0降低了雄性和雌性大鼠的呼吸暂停频率，并降低了雌性大鼠的呼吸频率。慢性孕酮治疗对雄性大鼠呼吸暂停频率的降低作用比雌性大鼠更有效，但在雌性大鼠（而非雄性大鼠）中，急性注射咖啡因（治疗早产儿呼吸暂停的金标准）进一步降低了呼吸暂停频率。新生大鼠的呼吸暂停频率部分取决于别孕烯醇酮、GABA受体和孕酮受体之间的性别特异性平衡。
