Antagonism of progesterone receptor suppresses carotid body responses to hypoxia and nicotine in rat pups

Joseph, Vincent; Niane, Lalah M.; Bairam, Aïda

doi:10.1016/j.neuroscience.2012.01.041

Cited by 17 publications

(17 citation statements)

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“…In this model of vagotomized and chemodenervated cats, the effects of progesterone on respiratory activity is primarily mediated by the hypothalamus [5], but the injection of progesterone in the NTS also increases respiratory activity [6]. Chronic treatment with mifepristone in newborn rats abolished carotid body responses to hypoxia [12], while progesterone treatment in adult cats enhances the carotid body response to hypoxia [7]. Progesterone combined with estradiol in rats enhances ventilation by decreasing the synthesis of the inhibitory neurotransmitter dopamine in the carotid body [32], which is consistent with the effect of the progesterone receptor on the expression of tyrosine hydroxylase [33], the rate-limiting enzyme in dopamine synthesis.…”

Section: Discussionmentioning

confidence: 93%

The Nuclear Progesterone Receptor Reduces Post-Sigh Apneas during Sleep and Increases the Ventilatory Response to Hypercapnia in Adult Female Mice

et al. 2014

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We tested the hypothesis that the nuclear progesterone receptor (nPR) is involved in respiratory control and mediates the respiratory stimulant effect of progesterone. Adult female mice carrying a mutation in the nPR gene (PRKO mice) and wild-type controls (WT) were implanted with an osmotic pump delivering vehicle or progesterone (4 mg/kg/day). The mice were instrumented with EEG and neck EMG electrodes connected to a telemetry transmitter. The animals were placed in a whole body plethysmograph 7 days after surgery to record ventilation, metabolic rate, EEG and neck EMGs for 4 consecutive hours. The animals were exposed to hypercapnia (5% CO2), hypoxia (12% O2) and hypoxic-hypercapnia (5% CO2+12% O2–5 min each) to assess chemoreflex responses. EEG and EMG signals were used to characterize vigilance states (e.g., wake, non-REM, and REM sleep). PRKO mice exhibited similar levels of minute ventilation during non-REM and REM sleep, and higher frequencies of sighs and post-sigh apneas during non-REM sleep compared to WT. Progesterone treatment increased minute ventilation and metabolic rate in WT and PRKO mice during non-REM sleep. In WT mice, but not in PRKO mice, the ventilation under hypercapnia and hypoxic hypercapnia was enhanced after progesterone treatment. We conclude that the nPR reduces apnea frequency during non-REM sleep and enhances chemoreflex responses to hypercapnia after progesterone treatment. These results also suggest that mechanisms other than nPR activation increase metabolic rate in response to progesterone treatment in adult female mice.

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Section: Discussionmentioning

confidence: 93%

The Nuclear Progesterone Receptor Reduces Post-Sigh Apneas during Sleep and Increases the Ventilatory Response to Hypercapnia in Adult Female Mice

et al. 2014

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“…We previously reported that mifepristone administration reduces the carotid sinus nerve response to hypoxia (Joseph et al . ), which is thought to play an important role in the early phase of the HVR. Accordingly, we focused the present study on the steady‐state phase of the HVR, mostly characterized in neonates by central respiratory inhibition (Bissonnette, ).…”

Section: Discussionmentioning

confidence: 99%

“…We showed previously, in newborn rats, that daily administration of mifepristone, a non‐specific progesterone receptor antagonist, dramatically decreases the carotid sinus nerve response to hypoxia (Joseph et al . ), suggesting a key contribution of endogenous progesterone for adequate development of the respiratory response to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

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

Potvin

Rossignol

Uppari

et al. 2014

Experimental Physiology

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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.

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“…31.1 ). We used the standard in vitro recording of the CSN activity, as previously described (Joseph et al 2012 ). In brief, the preparation was transferred to a recording chamber, thermostated at 36 °C (TC2Bip temperature controller; Cell Micro-Controls; Norfolk, VA, USA), and superfused at a fl ow rate of 6 mL/min with Tyrode solution bubbled with 5 % CO 2 balance in O 2 ; pH 7.4.…”

Section: Ex Vivo Electrophysiological Recording Of the Carotid Sinus mentioning

confidence: 99%

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

Iturri

Joseph

Rodrigo

et al. 2015

Advances in Experimental Medicine and Biology

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The carotid body is the main mammalian oxygen-sensing organ regulating ventilation. Despite the carotid body is subjected of extensive anatomical and functional studies, little is yet known about the molecular pathways signaling the neurotransmission and neuromodulation of the chemoreflex activity. As kinases are molecules widely involved in motioning a broad number of neural processes, here we hypothesized that pathways of protein kinase B (AKT) and extracellular signal-regulated kinases ½ (ERK1/2) are implicated in the carotid body response to hypoxia. This hypothesis was tested using the in-vitro carotid body/carotid sinus nerve preparation ("en bloc") from Sprague Dawley adult rats. Preparations were incubated for 60 min in tyrode perfusion solution (control) or containing 1 μM of LY294002 (AKT inhibitor), or 1 μM of UO-126 (ERK1/2 inhibitor). The carotid sinus nerve chemoreceptor discharge rate was recorded under baseline (perfusion solution bubbled with 5 % CO(2) balanced in O(2)) and hypoxic (perfusion solution bubbled with 5 % CO(2) balanced in N(2)) conditions. Compared to control, both inhibitors significantly decreased the normoxic and hypoxic carotid body chemoreceptor activity. LY294002- reduced carotid sinus nerve discharge rate in hypoxia by about 20 %, while UO-126 reduces the hypoxic response by 45 %. We concluded that both AKT and ERK1/2 pathways are crucial for the carotid body intracellular signaling process in response to hypoxia.

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Antagonism of progesterone receptor suppresses carotid body responses to hypoxia and nicotine in rat pups

Cited by 17 publications

References 50 publications

The Nuclear Progesterone Receptor Reduces Post-Sigh Apneas during Sleep and Increases the Ventilatory Response to Hypercapnia in Adult Female Mice

The Nuclear Progesterone Receptor Reduces Post-Sigh Apneas during Sleep and Increases the Ventilatory Response to Hypercapnia in Adult Female Mice

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

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

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