Endothelin inhibits thick ascending limb chloride flux via ETB receptor-mediated NO release
Endothelin inhibits thick ascending limb chloride flux via ETB receptor-mediated NO release
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DOI：
10.1152/ajprenal.2000.279.2.f326
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发表时间：
2000-08-01
影响因子：
4.2
通讯作者：
Garvin, JL
中科院分区：
文献类型：
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作者：
Plato, CF;Pollock, DM;Garvin, JL
内皮素-1 (ET-1) 抑制肾单位各节段的转运，亨利环升支粗管 (TALH) 表达 ET-1 受体。在许多组织中，ETB 受体的激活会刺激 NO 的释放，我们最近报道内源性 NO 会抑制 TALH 氯化物通量 (J(Cl))。然而，ET-1 和 NO 在控制肾单位运输中的关系尚未得到广泛研究。我们假设 ET-1 通过激活 ETB 受体和释放 NO 来减少皮质 TALH 的 NaCl 转运。外源 ET-1 (1 nM) 将 J(Cl) 从 118.3 +/- 15.0 降低至 62.7 +/- 13.6 pmol。毫米（-1）。 min(-1)（减少 48.3 +/- 8.2%），而去除 ET-1 则使另一组肾小管中的 J(Cl) 从 87.6 +/- 10.7 增加到 115.2 +/- 10.3 pmol。毫米（-1）。分钟(-1)（增加 34.5 +/- 6.2%）。为了确定 NO 是否介导 ET-1 对 J(Cl) 的抑制作用，我们检测了用 N-G-硝基-L-精氨酸甲酯 (L-NAME) 抑制 NO 合酶 (NOS) 对 ET-1 诱导的 J(Cl) 变化的影响。 L-NAME (5 mM) 完全阻止 ET-1 诱导的 J(Cl) 减少，而 D-NAME 则不然。单独的 L-NAME 对 J(Cl) 没有影响。这些数据表明 ET-1 的作用是由 NO 介导的。用 BQ-788 阻断 ETB 受体可阻止 1 nM ET-1 的抑制作用。用sarafotoxin S6c 激活ETB 受体模拟了ET-1 对J(Cl) 的抑制作用（从120.7 +/- 12.6 到75.4 +/- 13.3 pmol . mm(-1) . min(-1)）。相反，BQ-610的ETA受体拮抗作用并不能阻止ET-1介导的TALH J(Cl)抑制(从96.5+/-10.4到69.5+/-8.6pmol.mm(-1).min(-1))。内皮素使细胞内钙从 96.9 +/- 14.0 增加到 191.4 +/- 11.9 nM，增加了 110.8 +/- 26.1%。我们得出结论，外源性内皮素通过激活 ETB 受体、增加细胞内钙浓度和刺激 NO 释放来间接降低 TALH J(Cl)。这些数据表明，内皮素充当 TALH NO 合成的生理调节剂，从而抑制氯离子转运并有助于体内观察到的 ET-1 的利尿钠作用。
Endothelin-1 (ET-1) inhibits transport in various nephron segments, and the thick ascending limb of the loop of Henle (TALH) expresses ET-1 receptors. In many tissues, activation of ETB receptors stimulates release of NO, and we recently reported that endogenous NO inhibits TALH chloride flux (J(Cl)). However, the relationship between ET-1 and NO in the control of nephron transport has not been extensively studied. We hypothesized that ET-1 decreases NaCl transport by cortical TALHs through activation of ETB receptors and release of NO. Exogenous ET-1 (1 nM) decreased J(Cl) from 118.3 +/- 15.0 to 62.7 +/- 13.6 pmol . mm(-1) . min(-1) (48.3 +/- 8.2% reduction), whereas removal of ET-1 increased J(Cl) in a separate group of tubules from 87.6 +/- 10.7 to 115.2 +/- 10.3 pmol . mm(-1) . min(-1) (34.5 +/- 6.2% increase). To determine whether NO mediates the inhibitory effects of ET-1 on J(Cl), we examined the effect of inhibiting of NO synthase (NOS) with N-G-nitro-L-arginine methyl ester (L-NAME) on ET-1-induced changes in J(Cl). L-NAME (5 mM) completely prevented the ET-1-induced reduction in J(Cl), whereas D-NAME did not. L-NAME alone had no effect on J(Cl). These data suggest that the effects of ET-1 are mediated by NO. Blockade of ETB receptors with BQ-788 prevented the inhibitory effects of 1 nM ET-1. Activation of ETB receptors with sarafotoxin S6c mimicked the inhibitory effect of ET-1 on J(Cl) (from 120.7 +/- 12.6 to 75.4 +/- 13.3 pmol . mm(-1) . min(-1)). In contrast, ETA receptor antagonism with BQ-610 did not prevent ET-1-mediated inhibition of TALH J(Cl) (from 96.5 +/- 10.4 to 69.5 +/- 8.6 pmol . mm(-1) . min(-1)). Endothelin increased intracellular calcium from 96.9 +/- 14.0 to 191.4 +/- 11.9 nM, an increase of 110.8 +/- 26.1%. We conclude that exogenous endothelin indirectly decreases TALH J(Cl) by activating ETB receptors, increasing intracellular calcium concentration, and stimulating NO release. These data suggest that endothelin acts as a physiological regulator of TALH NO synthesis, thus inhibiting chloride transport and contributing to the natriuretic effects of ET-1 observed in vivo.