Renal medullary endothelin B receptors (ETB) mediate sodium excretion and blood pressure (BP) control. Several animal models of hypertension have impaired renal medullary ETB function. We found that 4-week high-caloric diet elevated systolic BP in Dahl salt-sensitive (Dahl S) rats (126±2 vs. 143±3 mm Hg, p<0.05). We hypothesized that renal medullary ETB function is dysfunctional in DS rats fed a high-caloric diet. We compared the diuretic and natriuretic response to intramedullary infusion of ETB agonist sarafotoxin 6c (S6c) in DS rats fed either a normal or high-caloric diet for 4 weeks. Urine was collected during intramedullary infusion of saline for baseline collection followed by intramedullary infusion of either saline or S6c. We first examined the ETB function in DS rats fed a normal diet. S6c increased urine flow (2.7±0.3 μl/min during baseline vs. 5.1±0.6 μl/min after S6c; p<0.05; n=5) and sodium excretion (0.28±0.05 vs. 0.81±0.17 μmol/min; p<0.05), suggesting that DS rats have renal medullary ETB function. However, DS rats fed a high-caloric diet displayed a significant increase in urine flow (2.7±0.4 vs. 4.2±0.4 μl/min, baseline vs. S6c infusion, respectively; p<0.05, n=6), but no significant change in sodium excretion in response to S6c (0.32±0.06 vs. 0.45±0.10 μmol/min). These data demonstrate that renal medullary ETB function is impaired in DS rats fed a high-caloric diet, which may be contributed to the elevation of blood pressure during high-caloric feeding in this model., W. Kittikulsuth, K. A. Hyndman, J. S. Pollock, D. M. Pollock., and Seznam literatury
The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O2) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ETB mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ETB pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH., J. Honda, T. Kimura, S. Sakai, H. Maruyama, K. Tajiri, N. Murakoshi, S. Homma, T. Miyauchi, K. Aonuma., and Seznam literatury