Johns Douglas G, Ao Zhaohui, Heidrich Bradley J, Hunsberger Gerald E, Graham Taylor, Payne Lisa, Elshourbagy Nabil, Lu Quinn, Aiyar Nambi, Douglas Stephen A
Vascular Biology and Thrombosis Department, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA.
Biochem Biophys Res Commun. 2007 Jun 22;358(1):145-9. doi: 10.1016/j.bbrc.2007.04.079. Epub 2007 Apr 19.
Dendroaspis natriuretic peptide (DNP) is a newly-described natriuretic peptide which lowers blood pressure via vasodilation. The natriuretic peptide clearance receptor (NPR-C) removes natriuretic peptides from the circulation, but whether DNP interacts with human NPR-C directly is unknown. The purpose of this study was to test the hypothesis that DNP binds to NPR-C. ANP, BNP, CNP, and the NPR-C ligands AP-811 and cANP(4-23) displaced [(125)I]-ANP from NPR-C with pM-to-nM K(i) values. DNP displaced [(125)I]-ANP from NPR-C with nM potency, which represents the first direct demonstration of binding of DNP to human NPR-C. DNP showed high pM affinity for the GC-A receptor and no affinity for GC-B (K(i)>1000 nM). DNP was nearly 10-fold more potent than ANP at stimulating cGMP production in GC-A expressing cells. Blockade of NPR-C might represent a novel therapeutic approach in augmenting the known beneficial actions of DNP in cardiovascular diseases such as hypertension and heart failure.
树眼镜蛇利钠肽（DNP）是一种新发现的利钠肽，它通过血管舒张作用降低血压。利钠肽清除受体（NPR-C）可从循环中清除利钠肽，但DNP是否直接与人NPR-C相互作用尚不清楚。本研究的目的是验证DNP与NPR-C结合的假说。心房钠尿肽（ANP）、脑钠肽（BNP）、C型钠尿肽（CNP）以及NPR-C配体AP-811和cANP(4-23)以皮摩尔到纳摩尔的解离常数（K(i)）值将[¹²⁵I]-ANP从NPR-C上置换下来。DNP以纳摩尔效力将[¹²⁵I]-ANP从NPR-C上置换下来，这是DNP与人NPR-C结合的首次直接证明。DNP对鸟苷酸环化酶-A（GC-A）受体表现出高皮摩尔亲和力，对GC-B无亲和力（K(i)>1000 nM）。在刺激表达GC-A的细胞产生环磷酸鸟苷（cGMP）方面，DNP的效力比ANP高近10倍。阻断NPR-C可能是一种新的治疗方法，可增强DNP在高血压和心力衰竭等心血管疾病中的已知有益作用。
