RESUMO
NPCdc is a synthetic natriuretic peptide that was originally derived from another peptide, the NP2_Casca, isolated from Crotalus durissus cascavella venom. These molecules share 70% structural homology with natriuretic peptides obtained from different species, including humans. NP2_Casca induces vasorelaxation and increases nitric oxide levels independently of natriuretic peptide receptors A and B. This study aimed to investigate whether NPCdc-induced hypotension in control rats and rats with a reduced kidney mass is associated with effects on the glomerular filtration rate, NADPH oxidase activity and components downstream of natriuretic peptide receptor C (NPR-C). Anaesthetized Wistar rats that were subjected to a sham operation and 5/6 nephrectomy (5/6Nx) were infused with saline (vehicle) or NPCdc (7.5⯵g/kg/min) for 70â¯min. The NPCdc treatment decreased the mean arterial pressure and NADPH oxidase activity while simultaneously increasing the glomerular filtration rate, fractional Na+ excretion and nitric oxide level. After 70â¯min, the levels of p-AKT Ser-473, p-eNOS Ser-1177, p-nNOS Ser-1417 and p-iNOSTyr-151 were not affected. However, p-ERK1/2 Thr-202/Tyr-204 levels were altered. Thus, nitric oxide and components of NPR-C signalling mediate the effects of NPCdc. The results suggest a potential therapeutic application of this peptide for cardiorenal syndrome.
Assuntos
Aorta/efeitos dos fármacos , Rim/efeitos dos fármacos , Peptídeo Natriurético Tipo C/farmacologia , Nefrectomia , Óxido Nítrico/metabolismo , Animais , Aorta/citologia , Aorta/metabolismo , Aorta/fisiologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Rim/citologia , Rim/metabolismo , Rim/fisiologia , Masculino , NADPH Oxidases/metabolismo , Peptídeo Natriurético Tipo C/síntese química , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, µ and δ opioid receptors. Since the peripheral and central antinociception induced by PnPP-19 involves opioid activation, the aim of this work was to identify whether this synthetic peptide could directly activate opioid receptors and investigate the subtype selectivity for µ-, δ- and/or κ-opioid receptors. Furthermore, we also studied the modulation of calcium influx driven by PnPP-19 in dorsal root ganglion neurons, and analyzed whether this modulation was opioid-mediated. PnPP-19 selectively activates µ-opioid receptors inducing indirectly inhibition of calcium channels and hereby impairing calcium influx in dorsal root ganglion (DRG) neurons. Interestingly, notwithstanding the activation of opioid receptors, PnPP-19 does not induce ß-arrestin2 recruitment. PnPP-19 is the first spider toxin derivative that, among opioid receptors, selectively activates µ-opioid receptors. The lack of ß-arrestin2 recruitment highlights its potential for the design of new improved opioid agonists.