Chen Horng H, Lainchbury John G, Burnett John C
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
J Am Coll Cardiol. 2002 Sep 18;40(6):1186-91. doi: 10.1016/s0735-1097(02)02127-7.
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.
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).
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 microg/kg/min) (Pfizer, Sandwich United Kingdom).
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.
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.
本研究的目的是首次确定利钠肽（NP）受体和中性内肽酶（NEP）在介导和调节新型治疗性合成利钠肽——黑曼巴利钠肽（DNP）的肾脏作用中的作用。
最近的报告提高了一种新描述的合成NP——DNP的治疗潜力。黑曼巴利钠肽是一种38个氨基酸的肽，最近从绿曼巴蛇（Dendroaspis augusticeps）的毒液中分离出来。
将合成的DNP以5 ng/kg/分钟的剂量经肾内给予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只犬接受NEP抑制剂坎多沙坦酯（8和80 μg/kg/分钟）输注（辉瑞公司，英国桑威奇）。
与基线相比，肾内给予DNP导致显著的利钠作用，伴有尿环磷酸鸟苷排泄量（UcGMPV）增加、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）降低。HS-142-1减弱了对DNP的利钠反应，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抑制剂均未增强DNP的肾脏作用。
我们报告NP受体阻断减弱了合成DNP的肾脏作用，且NEP抑制剂未改变对DNP的肾脏反应。后一发现是合成DNP的独特特性，与其他已知NP不同，支持其作为治疗剂的潜力。
