Modulation Of Hypoxia On Endothelin-1 Expression

ET-1, an important peptide, is related with neuroendocrinology system and chronic heart failure. It requires the maintenance of homeostasis proceeding. When the body is exposed to the stress such as hypoxia and stretch, the expression of ET-1 would change consequently. In the past years, ET-1 has been found in several non-vascular tissues, including those of the central nervous system (CNS), and at present, many researches show that ET-1 plays a neuromodulatory role. It has been shown that ET-1 (10^-10 to 10^-8 M) or ET-1 (0.1 to 1 mM) stimulates the release of arginine vasopressin (AVP) and substance P (SP) from a perifused rat hypothalamus.Hypoxia, one of the environmental factors in plateau, is due to a lowered oxygen pressure, which leads to oxygen deficiency of the whole organism, and even in tissues and cells, consequently disturbs physiological activities and does harm to health. Hypoxia will enhance CRF expression and induce the response of the hypothalamic -pituitary - adrenal (HPA) axis and endocrine systems. This study aims at determining the patterns of endothelin-1 (ET-1) response and correlation with corticotropin-releasing factor (CRF) and CRF receptor subtype 1(CRFR1) or NF-κB activated by hypoxia.To investigate how CRF R1 modulates the expression of ET-1 in PVN of the rat, we test ET-1 protein by immunohistochemistry and ET-1 mRNA by in situ hybridization after i.p. CRF Rl antagonist in rats. The ET-1 protein in the heart or skeleton muscle of three mammals(mice, M. oeconomus and O. curzoniae) were assayed by RIA, and the HIF-1α expression was tested by Western Blot.The results are as followed:1) Effects of continual hypoxia on the ET-1 and CRF expression in the rat.The immunoreactive ET-1 protein in PVN of the hypothalamus showed a significant decrease for 5 d following CHAH5km, this hypoxia did not cause statistical difference of ET-1 level for other exposure periods although showing a decreased tendency. CHAH5km for 1d and 2d decreased CRF peptide level in PVN. However, thehypoxia for 5d and lOd significantly increased CRF. Prolonged exposure to CHAH5km for 15 and 25d did not alter CRF peptide level in PVN. The CHAH5km increased plasma corticosterone levels for Id, 2d, 5d, lOd, and 15d, respectively, the peak of the plasma corticosterone occurred at 5 and 10 d, and returned to the control level at 25 d.The CRF peptide was increased by CHAH5km for 5d. This increase was markedly abolished by a daily pretreatment with CP-154, 526, a CRFR1 antagonist. CRF mRNA expression in PVN markedly increased by CHAH5km for 5d. A preinjection of CP-154, 526 following the hypoxia exposure caused a decrease in CRF mRNA expression in PVN showing an abolished action of the increased CRFmRNA by CRFR1 antagonist. The plasma corticosterone level in the group of CHAH5km for 5d was remarkably increased. However, the daily treatment with CRFR1 antagonist following CHAH5km resulted in the decreased corticosterone. The immunoreactivity of ET-1 was decreased remarkably. This hypoxia-caused ET-1 decrease, however, was reversed and increased dramatically by following CRFR1 antagonist treatment. ET-1 mRNA in PVN was increased remarkably, which was reversed by CRFR1 antagonist treatment.2) Effects of acute hypoxia on the ET-1 and HIF-la expression in the heart of the mice, M. oeconomus and O. curzoniae.By using an intraperitoneal injection of C0CI2 (20, 40 and 60 mg/kg), ET-1 and HIF-la expression in mice heart markedly increased via an injection of three doses of C0CI2. ET-1 expression increased significantly with the dose of 60 mg/kg and HIF-la expression increased significantly with the dose of 40 mg/kg and 60 mg/kg in M. oeconomus. C0CI2 had no significant role in O. curzoniae.ET-1 and HIF-la expression in mice heart markedly increased with 2.3km, 5km and 7km hypoxia for 6h, and with 7km hypoxia and the subcutaneous of NF-k B antagonist the ET-1 and HIF-la expression increased markedly. In M. oeconomus, ET-1 expression increased following 5km, 7km and the 7km antagonist and HIF-la expression increased following 7km and the 7km antagonist. However, ET-1 and HIF-la expression increased only following 7km and the 7km antagonist in O. curzoniae.3) Effects of acute hypoxia on the ET-1 and HIF-la expression in the skeleton muscle of the mice, M. oeconomus and O. curzoniae.By using an intraperitoneal injection of C0CI2 (20, 40 and 60 mg/kg), ET-1 and HIF-la expression in mice heart markedly increased via an injection of three doses of C0CI2. ET-1 expression increased significantly with the dose of 60 mg/kg and HIF-la expression increased significantly with the dose of 40 mg/kg and 60 mg/kg in M. oeconomus. C0CI2 had no significant role in O. curzoniae.ET-1 and HIF-la expression in mice heart markedly increased with 2.3km, 5km and 7km hypoxia for 6h, and with 7km hypoxia and the subcutaneous of NF-k B antagonist the ET-1 and HIF-la expression increased markedly. In M. oeconomus, ET-1 expression increased following 5km, 7km and the 7km antagonist and HIF-la expression increased following 5km, 7km, 5km antagonist and the 7km antagonist. However, ET-1 and HIF-la expression increased only following 7km and the 7km antagonist in O. curzoniae.Those data suggest that:1) Continual hypoxia induced the ET-1 expression in PVN of rat hypothalamus.2) CRFR1 modulated the ET-1 expression under the continual hypoxia in PVN of rat hypothalamus.3) Acute hypoxia induced the ET-1 expression in the in the heart or skeleton muscle of the mice, M. oeconomus and O. curzoniae.4) HIF-la and NF-k B might modulated the ET-1 expression in the heart or skeleton muscle of the mice, M. oeconomus and O. curzoniae.