Reduced hypoxic ventilatory response in newborn mice knocked‐out for the progesterone receptor

Abstract

New Findings r What is the central question of this study?Progesterone has been proposed as an alternative to xanthine therapy for the treatment of idiopathic apnoeas in preterm neonates, but our knowledge of the respiratory function of progesterone in neonates is limited. We therefore asked whether endogenous progesterone is an efficient respiratory stimulant in newborn mice. r What is the main finding and its importance?The present study shows that expression of the nuclear progesterone receptor is a key contributor to the hypoxic ventilatory response in newborn mice. This study will encourage further research on the role of other progesterone receptors in respiratory control in newborn mammals.Recent studies showed that progesterone stimulates the hypoxic ventilatory response and may reduce apnoea frequency in newborn rats, but so far we still do not know by what mechanisms and whether endogenous progesterone might contribute to respiratory control in neonates. We therefore determined the role of the nuclear progesterone receptor (PR; member of the steroid receptor superfamily) by using wild-type (WT) and PR knock-out (PRKO) mice at postnatal days (P) 1, 4 and 10. We measured the hypoxic ventilatory response (14 and 12% O 2 , 20 min each) and apnoea frequency in both male and female mice by using whole-body plethysmography. In response to hypoxia, WT male mice had a marked hypoxic ventilatory response at P1 and P10, but not at P4. At P1 and P10, PRKO male mice had a lower hypoxic ventilatory response than WT males. Wild-type female mice had a marked hypoxic ventilatory response at P10, but not at P1 and P4. At P1 and P10, PRKO female mice had a lower hypoxic ventilatory response than WT females. In basal conditions, apnoea frequency was similar in WT and PRKO mice at P1, P4 and P10. During hypoxia, apnoea frequency was higher in WT male mice compared with PRKO male mice and WT female mice at P1. We conclude that PR is a key contributor to the hypoxic ventilatory response in newborn mice, but PR deletion does not increase the frequency of apnoea during normoxia or hypoxia.

Neonatal stress affects the aging trajectory of female rats on the endocrine, temperature, and ventilatory responses to hypoxia

“…Regardless of the theoretical arguments, validation of any experimental technique is ultimately based on comparisons with other methods. We recently performed this exercise in mice, and data show that the open flow plethysmograph produces V T values that are very similar to those obtained with more direct methods such as "head-out" plethysmography (53). Placing a pneumotachograph on the trachea of an anesthetized animal is arguably the most direct (and accurate) method to measure V T , and in adult rats, the baseline values obtained with this method [0.7 Ϯ 0.13 ml/100 g; (22)] are similar to those reported in Table 1.…”

Respiratory regulation by steroids in newborn rats: a sex‐specific balance between allopregnanolone and progesterone receptors

“…It is worth mentioning that in newborn rats or mice, the values reported for V T using our set‐up are within the same range as those obtained with direct volume recordings with head‐out plethysmography systems (see discussion by Potvin et al . ).…”

“…,b), and there are sex‐specific effects of progesterone receptor deletion on the hypoxic ventilatory response in newborn mice (Potvin et al . ). Furthermore, in human neonates, mortality linked to respiratory disorders, hypoxia or asphyxia is almost 50% higher in males versus females (Mage & Donner, , ; Kouchi et al .…”

“…), but in newborns the frequency of apnoea is similar between nPR knockout and wild‐type mice (Potvin et al . ). It is thus tempting to suggest that in addition to the balance between allopregnanolone and progesterone, the regulation of breathing by progesterone is also the result of the activation of different types of receptors, including the nPR and mPR, with an apparent difference between males and females for the nPR.…”

Obstructive sleep apnea and hormones – a novel insight

“…Progesterone is associated with hyperventilation during pregnancy. In mice knocked down for the progesterone receptor, the reaction to hypoxia is reduced [27]. Driver et al .…”