Objective To investigate the potential molecular mechanism of endothelin-1 (ET-1) involved in cyclic intermittent hypoxia (CIH) induced carotid body chemoreceptor plasticity. Methods (1) Animal experiment: 32 male Sprague-Dawley (SD) rats were randomly divided into two groups: control group (Con) and CIH group (CIH), 16 rats per group. After 21 days of CIH exposure, each group (Con and CIH) was subdivided into 2 groups: tail vein injection of ET-1 (1 x 10^-6mol/kg body weight) or same volume of saline according to the above dose. After 30 minutes of injection, carotid bodies were collected and Western blotting was used to detect the change of tested proteins. (2) Carotid body organ culture: rat carotid bodies were isolated and cultured in the incubator, and treated with ET-1 (1×10^-4 mol/L) for different times (0 minute, 10 minutes, 60 minutes). The effect of ET-1 on the phosphorylation of p38 mitogenactivated protein kinase (p38 MAPK) was detected by Western blotting. Results (1) CIH increased the protein level of endothelin receptor A (ET-A)and ET-B in the rat carotid body. (2) Compared with the ET-1 injected Con group, phosphorylated protein kinase A (p-PKA), p-p38 MAPK, phosphorylated Ca ^2+/calmodulin-dependent protein kinase Ⅱ (p-CaMKⅡ) and phosphorylated cAMP response element-binding protein (p-CREB) and RhoA protein level were significantly up-regulated in ET-1 injected CIH rats. (3) Application of ET-1 to organ cultured carotid bodies resulted in the elevation of p-p38 MAPK in a time-dependent manner. Conclusion ET-1 may regulate CIH-induced carotid body chemoreflex plasticity through PKA/p38 MAPK/CaMKⅡ/CREB and RhoA signaling.