Membrane progesterone receptor-β, but not -α, in dorsal brain stem establishes sex-specific chemoreflex responses and reduces apnea frequency in adult mice

We tested the hypothesis that membrane progesterone receptors (mPR) contribute to respiratory control in adult male and female mice. Mice were implanted with osmotic minipumps for continuous infusion of small interfering RNA (siRNA) directed against mPR alpha, mPR beta, or a control solution in the fourth ventricle (to target brain stem respiratory areas) for 14 days. We then performed respiratory and metabolic recordings by whole body plethysmography at rest and in response to hypoxia (12% O-2) or hypercapnia (5% CO2, 5 min each). For each treatment, we have verified with immunohistochemistry that the staining intensity of mPR alpha or mPR beta in the brain stem is decreased. At rest, the siRNA against mPR alpha and mPR beta increased respiratory frequency in males only. The siRNA against mPR beta almost tripled the frequency of apneas in male and in female mice, while the siRNA against mPR alpha had no effect. Regarding respiratory chemoreflex, the siRNA against mPR beta suppressed the response to hypoxia in male and female mice and reduced by similar to 50% the response to hypercapnia, while the siRNA against mPR alpha had more limited effects. Interestingly, control females had higher ventilatory response to hypoxia and hypercapnia than males, and these sex-specific effects were suppressed by the siRNA against mPR beta, whereas they were still present after treatment with the siRNA against mPR alpha. We conclude that mPR beta reduces apnea frequency in male and female mice and establishes sex-specific ventilatory chemoreflex.