Touyz R M, Picard S, Schiffrin E L, Deschepper C F
Experimental Hypertension Laboratory, Institut de Recherches Cliniques de Montréal, Québec, Canada.
J Neurochem. 1997 Apr;68(4):1451-61. doi: 10.1046/j.1471-4159.1997.68041451.x.
There is growing evidence that cyclic GMP (cGMP) plays important roles in the brain. In cultured rat astrocytes, we observed that the cGMP-inducing C-type natriuretic peptide (CNP) and cGMP analogues caused a decrease in intracellular pH (pHi). To examine whether this effect was due to inhibition of an Na+/H+ exchanger (NHE), we acidified cells by replacing extracellular Na+ by choline and examined the kinetics of the pHi recovery that occurred on reintroduction of Na+ in the extracellular medium. Both CNP and amiloride analogues inhibited the Na(+)-dependent pHi recovery, even in the nominal absence of CO2/HCO3-. This indicated that CNP inhibited the activity of an exchanger that was Na(+)-dependent, HCO3(-)-independent, and sensitive to known inhibitors of NHE. However, comparison of the potencies of four distinct amiloride analogues revealed a pharmacological profile that was different from that of any other NHE characterized to date. cGMP mimicked the effect of CNP on sodium-dependent pHi recovery, but the native nucleotide was as potent as membrane-permeant analogues. Intracellularly produced cGMP was very rapidly exported out of astrocytes. Probenecid and niflumic acid slowed down the rate of cGMP egression and inhibited the effect of CNP on Na(+)-dependent recovery, but not that of extracellular cGMP. Altogether, our data indicate that cGMP inhibits a novel type of NHE in astrocytes via an extracellular site of action. If these results with primary cultures transfer to brain, this phenomenon may constitute a mechanism by which natriuretic peptides exert some of their actions in the brain, as pHi transients have been shown to modulate several important astrocytic functions.
越来越多的证据表明，环磷酸鸟苷（cGMP）在大脑中发挥着重要作用。在培养的大鼠星形胶质细胞中，我们观察到，诱导cGMP的C型利钠肽（CNP）和cGMP类似物会导致细胞内pH值（pHi）降低。为了研究这种效应是否是由于抑制了钠/氢交换体（NHE），我们用胆碱替代细胞外的钠使细胞酸化，并检测了在细胞外培养基中重新引入钠时pHi恢复的动力学。CNP和氨氯地平类似物均抑制了钠依赖性的pHi恢复，即使在名义上不存在二氧化碳/碳酸氢根的情况下也是如此。这表明CNP抑制了一种钠依赖性、碳酸氢根非依赖性且对已知NHE抑制剂敏感的交换体的活性。然而，对四种不同氨氯地平类似物效力的比较显示出一种药理学特征，与迄今为止所描述的任何其他NHE都不同。cGMP模拟了CNP对钠依赖性pHi恢复的作用，但天然核苷酸与膜通透性类似物的效力相同。细胞内产生的cGMP非常迅速地从星形胶质细胞中排出。丙磺舒和氟尼酸减慢了cGMP外流的速度，并抑制了CNP对钠依赖性恢复的作用，但不影响细胞外cGMP的作用。总之，我们的数据表明，cGMP通过细胞外作用位点抑制星形胶质细胞中一种新型的NHE。如果原代培养的这些结果能转化到大脑中，这种现象可能构成一种机制，通过该机制利钠肽在大脑中发挥其某些作用，因为pHi瞬变已被证明可调节几种重要的星形胶质细胞功能。
