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 % O(2)) 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. ET(B) 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 ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.
- MeSH
- exprese genu MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- hypoxie farmakoterapie metabolismus MeSH
- liraglutid farmakologie terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- plicní hypertenze farmakoterapie metabolismus MeSH
- receptor endotelinu B biosyntéza genetika MeSH
- receptor pro glukagonu podobný peptid 1 agonisté metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
To determine the relationship between hyperventilation and recovery of blood pH during recovery from a heavy exercise, short-term intense exercise (STIE) tests were performed after human subjects ingested 0.3 g · kg-1 body mass of either NaHCO3 (Alk) or CaCO3 (Pla). Ventilation (V . E) - CO2 output (V . co2) slopes during recovery following STIE were significantly lower in Alk than in Pla, indicating that hyperventilation is attenuated under the alkalotic condition. However, this reduction of the slope was the result of unchanged V . E and a small increase in V . co2. A significant correlation between V . E and blood pH was found during recovery in both conditions. While there was no difference between the V . E - pH slopes in the two conditions, V . E at the same pH was higher in Alk than in Pla. Furthermore, the values of pH during recovery in both conditions increased toward the preexercise levels of each condition. Thus, although V . E - V . co2 slope was decreased under the alkalotic condition, this could not be explained by the ventilatory depression attributed to increase in blood pH. We speculate that hyperventilation after the end of STIE is determined by the V . E - pH relationship that was set before STIE or the intensity of the exercise performed.
The purpose of this study was to examine how oxygen uptake (V . o2) in decrement-load exercise (DLE) is affected by changing rate of decrease in power output. DLE was performed at three different rates of decrease in power output (10, 20 and 30 watts·min-1: DLE10, DLE20 and DLE30, respectively) from power output corresponding to 90 % of peak V . o2. V . o2 exponentially increased and then decreased, and the rate of its decrease was reduced at low power output. The values of V . o2 in the three DLE tests were not different for the first 2 min despite the difference in power output. The relationship between V . o2 and power output below 50 watts was obtained as a slope to estimate excessive V . o2 (ex-V . o2) above 50 watts. The slopes were 10.0±0.9 for DLE10, 9.9±0.7 for DLE20 and 10.2±1.0 ml·min-1·watt-1 for DLE30. The difference between V . o2 estimated from the slope and measured V . o2 was defined as ex-V . o2. The peak value of ex-V . o2 for DLE10 (189±116 ml·min-1) was significantly greater than those for DLE20 and for DLE30 (93±97 and 88±34 ml·min-1). The difference between V . o2 in DLE and that in incremental-load exercise (ILE) below 50 watts (?V . o2) was greater in DLE30 and smallest in DLE10. There were significant differences in ?V . o2 among the three DLE tests. The values of ?V . o2 at 30 watts were 283±152 for DLE10, 413±136 for DLE20 and 483±187 ml·min-1 for DLE30. Thus, a faster rate of decrease in power output resulted in no change of V . o2 at the onset of DLE, smaller ex-V . o2 and greater ?V . o2. These results suggest that V . o2 is disposed in parallel in each motor unit released from power output or recruited in DLE.
The aim of this study was to determine whether excessive oxygen uptake (V . o2) occurs not only during exercise but also during recovery after heavy exercise. After previous exercise at zero watts for 4 min, the main exercise was performed for 10 min. Then recovery exercise at zero watts was performed for 10 min. The main exercises were moderate and heavy exercises at exercise intensities of 40 % and 70 % of peak V . o2, respectively. V . o2 kinetics above zero watts was obtained by subtracting V . o2 at zero watts of previous exercise (?V . o2). ? V . o2 in moderate exercise was multiplied by the ratio of power output performed in moderate and heavy exercises so as to estimate the ? V . o2 applicable to heavy exercise. The difference between ? V . o2 in heavy exercise and ? V . o2 estimated from the value of moderate exercise was obtained. The obtained V . o2 was defined as excessive V . o2. The time constant of excessive V . o2 during exercise (1.88±0.70 min) was significantly shorter than that during recovery (9.61±6.92 min). Thus, there was excessive V . o2 during recovery from heavy exercise, suggesting that O2/ATP ratio becomes high after a time delay in heavy exercise and the high ratio continues until recovery.
