MR effects on the peripheral stress response
In response to stressors, circuits converge on the brainstem to stimulate sympathetic nervous system activation (Herman et al. , 2016), and on the hypothalamic paraventricular nucleus to stimulate the HPA axis (Lightman, Birnie and Conway-Campbell, 2020). MRs can stimulate sympathetic outflow, as demonstrated by denervation studies in rat models for hypertension (Rahmouni et al. , 2001). MRs also crucially maintain the HPA axis set point, demonstrated by Mary Dallman’s study that reinstated the hypothalamic and pituitary set point in adrenalectomised rats with low dose corticosteroids (Dallman et al. , 1989). In a more physiological setting, the MR antagonist RU28318 increased basal HPA axis activity and potentiated the initial rise in ACTH and corticosterone secretion in response to stress (Ratka et al. , 1989; van Haarst, Oitzl and de Kloet, 1997). In humans, systemic treatment using MR antagonist spironolactone increased basal and stress induced cortisol secretion (Cornelisse, Joels and Smeets, 2011). In contrast, GR antagonism did not affect basal HPA axis activity but instead attenuated the initial HPA stress response and prolonged cortisol secretion by inhibiting GR negative feedback (Ratka et al. , 1989; van Haarst, Oitzl and de Kloet, 1997).