A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, ^1H N...A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, ^1H NMR and MS. The results of NHE1 inhibitory activity test showed that compounds I2, I3, I4, I6, and I7 possess more potent NHE1 inhibitory activity than cariporide.展开更多
Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It...Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.展开更多
文摘A series of novel derivatives of ligustrazine linked with substituted benzoyl guanidine were synthesized. These compounds have not been reported in literature, and their chemical structures were confirmed by IR, ^1H NMR and MS. The results of NHE1 inhibitory activity test showed that compounds I2, I3, I4, I6, and I7 possess more potent NHE1 inhibitory activity than cariporide.
基金supported by the National Natural Science Foundation of China(30900646 and 81241004)
文摘Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.
