학술논문
NPCdc, a synthetic natriuretic peptide, is a substrate to neprilysin and enhances blood pressure-lowering induced by enalapril in 5/6 nephrectomized rats.
Document Type
Article
Author
Source
Subject
*ANGIOTENSIN I
*RATS
*NEPRILYSIN
*FLUORESCENCE resonance energy transfer
*LABORATORY rats
*AMINO acid sequence
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Language
ISSN
0041-0101
Abstract
NPCdc is a natriuretic peptide synthesized from the amino acid sequence of the Crotalus durissus cascavella snake venom peptide, NP2Casca. NPCdc presents hypotensive and antioxidants effects. This study aimed to investigate in vivo whether angiotensin I-converting enzyme (ACE) inhibition would influence the impact of NPCdc in arterial pressure of rats submitted to 5/6 nephrectomy (Nx). Adult male Wistar rats following a 5/6 Nx were treated with enalapril (NxE group, 10 mg/kg/day, n = 9) or vehicle (Nx group, n = 8) for two weeks. On the 15th day after Nx, rats were anaesthetized and submitted to mean arterial pressure (MAP) determination before and after receiving two intravenous injections of saline (vehicle, n = 9) or NPCdc (0.3 μg/kg dissolved in saline, n = 18) separated by a 20-min interval. The kidneys were submitted to oxidative stress analysis. The basal MAP of the NxE group was nearly 20% lower (P < 0.05) than non-treated rats. NPCdc administration decreased the MAP in both groups; however, in the NxE group, the effects were observed only in the second injection. The peptide also decreased the NADPH oxidase activity in the renal cortex. Additionally, the hydrolysis of NPCdc by recombinant neprilysin (NEP) was monitored by mass spectrometry. NPCdc was cleaved by NEP at different peptides with an inhibition constant (Ki) of 1.5 μM, determined by a competitive assay using the NEP fluorescence resonance energy transfer (FRET) peptide substrate Abz-(d)Arg-Gly-Leu-EDDnp. Docking experiments confirmed the high affinity of NPCdc toward NEP. These findings provide new insights into the antihypertensive and antioxidant mechanism of action of NPCdc. Altogether, the results presented here suggest that NPCdc must be further studied as a potential therapy for cardiorenal syndromes. • NPCdc is a synthetic natriuretic peptide based on the sequence of NP2Casca. • NP2Casca is isolated from Crotalus durissus cascavella snake venom. • NPCdc reduces blood pressure in addition to enalapril in nephrectomized rats. • The antioxidant effect of NPCdc involves inhibition of NADPH oxidase activity. • NPCdc presents a high affinity to NEP and inhibits its catalytic activity. [ABSTRACT FROM AUTHOR]