Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide Dendroaspis natriuretic peptide
Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide Dendroaspis natriuretic peptide
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DOI：
10.1016/s0735-1097(02)02127-7
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发表时间：
2002-09-18
影响因子：
24
通讯作者：
Burnett, JC
中科院分区：
文献类型：
--
作者：
Chen, HH;Lainchbury, JG;Burnett, JC
目的 本研究的目的是首次明确利尿钠肽 (NP) 受体和中性肽链内切酶 (NEP) 在介导和调节 Dendroaspis 利尿钠肽 (DNP)（一种新的治疗性合成 NP）肾脏作用中的作用。 背景 最近的报告提出了一种新描述的合成 NP（称为 DNP）的治疗潜力。 Dendroaspis 利钠肽是最近从 Dendroaspis augusticeps（绿曼巴蛇）毒液中分离出的一种 38 个氨基酸的肽。 方法 将合成 DNP 以 5 ng/kg/min 的速度肾内给予 11 只正常麻醉犬，其中 5 只接受 NP 受体拮抗剂 HS-142-1（3 mg/kg 静脉推注），其余 6 只狗接受输注 NEP 抑制剂 Candoxatrilat（8 和 80 杯/公斤/分钟）（辉瑞公司，Sandwich 英国）。 结果 与基线相比，肾内 DNP 导致显着的尿钠排泄，与尿循环单磷酸鸟苷排泄 (UcGMPV)、肾小球滤过率 (GFR) 和肾血流量 (RBF) 增加以及远端钠重吸收分数 (FNaR) 减少相关。 HS-142-1 减弱对 DNP 的利尿钠反应，导致 UcGMPV、GFR 和 RBF 降低，远端 FNaR 增加。相比之下，低剂量和高剂量的NEP抑制剂并没有增强DNP的肾脏作用。结论我们报告说，NP受体阻断减弱了合成DNP的肾脏作用，并且NEP抑制剂没有改变肾脏对DNP的反应。后一个发现是合成 DNP 的独特性质，与其他已知的 NP 不同，支持其作为治疗剂的潜力。
OBJECTIVES The objectives of the current study were to define for the first time the roles of the natriuretic peptide (NP) receptors and neutral endopeptidase (NEP) in mediating and modulating the renal actions of Dendroaspis natriuretic peptide (DNP), a new therapeutic synthetic NP.BACKGROUND Recent reports have advanced the therapeutic potential of a newly described synthetic NP called DNP. Dendroaspis natriuretic peptide is a 38-amino acid peptide recently isolated from the venom of Dendroaspis augusticeps (the green mamba snake).METHODS Synthetic DNP was administered intra-renally at 5 ng/kg/min to 11 normal anesthetized dogs, 5 of which received the NP receptor antagonist HS-142-1 (3 mg/kg intravenous bolus) while the remaining 6 dogs received an infusion of the NEP inhibitor, candoxatrilat (8 and 80 mug/kg/min) (Pfizer, Sandwich United Kingdom).RESULTS Intra-renal DNP resulted in marked natriuresis associated with increased urinary cyclic guanosine monophosphate excretion (UcGMPV), glomerular filtration rate (GFR), and renal blood flow (RBF) and decreased distal fractional sodium reabsorption (FNaR) compared with baseline. HS-142-1 attenuated the natriuretic response to DNP, resulting in decreased UcGMPV, GFR, and RBF and increased distal FNaR. In contrast, low and high doses of NEP inhibitor did not potentiate the renal actions of DNP.CONCLUSIONS We report that the NP receptor blockade attenuated the renal actions of synthetic DNP and that the NEP inhibitor did not alter the renal response to DNP. This latter finding is a unique property of synthetic DNP, as distinguished from other known NPs, supporting its potential as a therapeutic agent.