Salt intake augments hypotensive effects of transient receptor potential vanilloid 4: functional significance and implication.
Salt intake augments hypotensive effects of transient receptor potential vanilloid 4: functional significance and implication.
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DOI：
10.1161/hypertensionaha.108.117499
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Wang DH
中科院分区：
文献类型：
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作者：
Gao F;Sui D;Garavito RM;Worden RM;Wang DH
为了验证瞬时受体电位香草酸4（TRPV 4）通道的激活传递了在盐负荷期间增强的兴奋作用的假设，雄性Wistar大鼠喂食正常的分别给予生理盐水（NS，0.5%）或高钠（HS，4%）饲料喂养3周（4α - PDD），一种特异性TRPV 4激活剂，在存在或不存在辣椒平（CAPZ），一种选择性TRPV 1阻断剂;钌红（RuR），一种TRPV 4阻断剂;或TRPV 4小发夹（sh）RNA，选择性敲低TRPV 4。4α-PDD（1、2.5或5 mg/kg，iv）呈剂量依赖性降低平均动脉压（MAP，p<0.05）。HS可增强4α-PDD的降压作用及4α-PDD介导的降钙素基因相关肽（CGRP）和P物质（SP）的释放（p<0.001）。RuR显著减弱（p<0.001），而CAPZ轻微减弱（p<0.05）HS和NS大鼠4α-PDD的降压作用。RuR单独增加HS和NS大鼠的基线MAP，前者的幅度更大（p< 0.05）。Western blot分析显示，HS增加了TRPV 4在背根神经节（DRG）和肠系膜动脉（MA）的表达（p<0.05），但对肾皮质和髓质无影响。基因沉默法显示TRPV 4 shRNA下调TRPV 4的表达，导致4α-PDD诱导的低血压减弱（p<0.05）。因此，TRPV 4活化降低了给予NS的大鼠的血压。HS增强感觉神经/肠系膜动脉中TRPV 4的表达和TRPV 4介导的降压效应和CGRP/SP释放，使得当TRPV 4被阻断时HS引起血压更大的升高。我们的数据表明，TRPV 4激活可能构成了一种补偿机制，防止盐诱导的血压升高。
To test the hypothesis that activation of the transient receptor potential vanilloid 4 (TRPV4) channel conveys a hypotensive effect that is enhanced during salt load, male Wistar rats fed a normal (NS, 0.5%) or high sodium (HS, 4%) diet for 3 weeks were given 4α-phorbol 12,13-didecanoate (4α – PDD), a specific TRPV4 activator, in the presence or absence of capsazepine (CAPZ), a selective TRPV1 blocker; ruthenium red (RuR), a TRPV4 blocker; or TRPV4 small hairpin (sh)RNA that selectively knockdowns TRPV4. 4α-PDD (1, 2.5, or 5 mg/kg, iv) dose-dependently decreased mean arterial pressure (MAP, p<0.05). HS enhanced 4α-PDD-induced depressor effects as well as 4α-PDD-mediated release of calcitonin gene related peptide (CGRP) and substance P (SP) (p<0.001). RuR markedly blunted (p<0.001), while CAPZ slightly attenuated (p<0.05), 4α-PDD-induced depressor effects in HS and NS rats. RuR alone increased baseline MAP in both HS and NS rats with a greater magnitude in the former (p< 0.05). Western blot analysis showed that HS increased TRPV4 expression in dorsal root ganglia (DRG) and mesenteric arteries (MA) (p<0.05) but not the renal cortex and medulla. Gene-silencing approach revealed that TRPV4 shRNA down-regulated TRPV4 expression leading to blunted 4α-PDD-induced hypotension (p<0.05). Thus, TRPV4 activation decreases blood pressure in rats given NS. HS enhances TRPV4 expression in sensory nerves/mesenteric arteries and TRPV4-mediated depressor effects and CGRP/SP release, in such that HS causes a greater increase in blood pressure when TRPV4 is blocked. Our data indicate that TRPV4 activation may constitute a compensatory mechanism in preventing salt-induced increases in blood pressure.