Corticotropin-Releasing Factor Receptor Subtypes In Rat Anterior Pituitary Mediate Responses Of Intermittent Hypoxia, Cold And Restraint Stress

High altitude hypoxia has long been considered important because large populations of people live at high altitude, and many others like to visit for traveling and climbing or athletic training. These will be exposed to depressed oxygen supply in response to altitude, which may be acute, chronic or intermittent.Corticotropin-releasing factor (CRF) family plays an important role in the control of stress-related behavior such as food intake and energy balance. Stress will enhance CRF expression and induce the response of the hypothalamic-pituitary-adrenal (HPA) axis and endocrine systems.We had previously demonstrated that continual hypoxia stimulated CRF and CRF mRNA in hypothalamus, and enhanced plasma ACTH and corticosterone of rats. This study demonstrated that the expression of CRF receptor type 1 (CRF Rl) and CRF receptor type 2 (CRF R2) mRNAs in the rat anterior pituitary changed during intermittent hypoxia, cold and restraint, using in situ autoradiograph. In addition, we tested CRF Rl and CRF R2 mRNA expression under cold, intermittent hypoxia, restraint, cold+ intermittent hypoxia, and intermittent hypoxia+restraint for 2d (4h/d).To investigate how CRF modulates the expression of CRF receptors in the rat anterior pituitary, we test pituitary CRF Rl mRNA and CRF R2 mRNA by RT-PCR after i.p. CRF Rl antagonist in rats.The results are as followed:(1) Hypoxia equivalent to an altitude of around 2km (16.0% O2) caused a biphasic change in both CRFR1 and R2 mRNA, there being an initial significant decline on day land then an enhancement by day 2. The increase of both receptor subtypes mRNA was relatively well maintained up to 15 days in rats exposed to 2km intermittently.(2) CRF R2 mRNA at 5km for 1 d was markedly decreased, but was increased for 2d (P<0.001), 5d (P<0.01) and returned to control level for 10 and 15d.(3) 2 km of hypoxia produced a no significant body weight gain, but food intakedecreased. However, 5km of the hypoxia reduced markedly body weight gain (recovered after 15d).(4) The CRF Rl mRNA was significantly increased by restraint, intermittent hypoxia, the combination of restraint +hypoxia and the combination of cold + hypoxia, but decreased by sole cold. The CRF R2 mRNA was significantly increased by all the single stressor and by the combination of stressors.(5) After i.p. CRF Rl antagonist, pituitary CRF Rl mRNA was significantly decreased during 5km hypoxia for 5d.Those data suggest that:(1) Intermittent hypoxia caused a biphasic change in both CRF Rl and R2 mRNA, there being an initial significant decline on day 1 and then an enhancement by day 2 to 15.(2) Intermittent hypoxia reduced body weight gain and decreased food intake.(3) An upregulation of CRF Rl and CRF R2 mRNA expressions in pituitary were triggered by, intermittent hypoxia, restraint, cold + hypoxia and restraint + hypoxia except CRF Rl mRNA in cold stress, that activate pituitary-adrenal cortex; The responses of CRF Rl mRNA to restraint and restraint + intermittent hypoxia are most powerful than to other stressors, suggested that restraint enhance the response of hypoxia.(4) CRF R2 mRNA expression upregulated by intermittent hypoxia may be attenuated by the combination of hypoxia + restraint and cold + hypoxia.(5) CRF upregulate CRF receptors in 5km intermittent hypoxia for 5d.