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EXPERIMENTAL STUDY

Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide dendroaspis natriuretic peptide

^* Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

Manuscript received March 11, 2002; revised manuscript received May 7, 2002, accepted May 23, 2002.

^* Reprint requests and correspondence: Dr. Horng H. Chen, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First Street Southwest, Rochester, Minnesota 55905, USA.
chen.horng{at}mayo.edu

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 µg/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.

Abbreviations and Acronyms   ANP   atrial natriuretic peptide   BNP   brain natriuretic peptide   cGMP   cyclic guanosine monophosphate   CHF   congestive heart failure   CLLi   lithium clearance   CLNa   sodium clearance   CNP   C-type natriuretic peptide   DFNaR   distal fractional sodium reabsorption   DNP   Dendroaspis natriuretic peptide   GFR   glomerular filtration rate   MAP   mean arterial blood pressure   NEP   neutral endopeptidase 24-11   RBF   renal blood flow   UcGMPV   urinary cGMP excretion   UNaV   urinary sodium excretion

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