NONO2P, a novel nitric oxide donor, causes vasorelaxation through NO/sGC/PKG pathway, K + channels opening and SERCA activation.

Autor: Moraes RA; Laboratory of Cardiovascular Physiology and Pharmacology, Bioregulation Department, Federal University of Bahia, UFBA, Salvador, Bahia, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil., Brito DS; Laboratory of Cardiovascular Physiology and Pharmacology, Bioregulation Department, Federal University of Bahia, UFBA, Salvador, Bahia, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil., Araujo FA; Laboratory of Cardiovascular Physiology and Pharmacology, Bioregulation Department, Federal University of Bahia, UFBA, Salvador, Bahia, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil., Jesus RLC; Laboratory of Cardiovascular Physiology and Pharmacology, Bioregulation Department, Federal University of Bahia, UFBA, Salvador, Bahia, Brazil., Silva LB; Laboratory of Cardiovascular Physiology and Pharmacology, Bioregulation Department, Federal University of Bahia, UFBA, Salvador, Bahia, Brazil., Sá DS; Federal Institute of Bahia, IFBA, Salvador, BA, Brazil., Silva da Silva CD; Federal Institute of Bahia, IFBA, Salvador, BA, Brazil., Pernomian L; Department of Cell Biology and Anatomy, University of South Carolina, Columbia, SC, USA; Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC, USA., Wenceslau CF; Department of Cell Biology and Anatomy, University of South Carolina, Columbia, SC, USA; Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC, USA., Priviero F; Department of Cell Biology and Anatomy, University of South Carolina, Columbia, SC, USA; Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC, USA., Webb RC; Department of Cell Biology and Anatomy, University of South Carolina, Columbia, SC, USA; Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC, USA., Silva DF; Laboratory of Cardiovascular Physiology and Pharmacology, Bioregulation Department, Federal University of Bahia, UFBA, Salvador, Bahia, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, BA, Brazil. Electronic address: darizy.silva@ufba.br.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Sep 15; Vol. 979, pp. 176822. Date of Electronic Publication: 2024 Jul 22.
DOI: 10.1016/j.ejphar.2024.176822
Abstrakt: Background & Aims: The treatment of cardiovascular diseases (CVD) could greatly benefit from using nitric oxide (NO) donors. This study aimed to investigate the mechanisms of action of NONO2P that contribute to the observed responses in the mesenteric artery. The hypothesis was that NONO2P would have similar pharmacological actions to sodium nitroprusside (SNP) and NO.
Methods: Male Wistar rats were euthanized to isolate the superior mesenteric artery for isometric tension recordings. NO levels were measured using the DAF-FM/DA dye, and cyclic guanosine monophosphate (cGMP) levels were determined using a cGMP-ELISA Kit.
Results: NONO2P presented a similar maximum efficacy to SNP. The free radical of NO (NO • ) scavengers (PTIO; 100 μM and hydroxocobalamin; 30 μM) and nitroxyl anion (NO - ) scavenger (L-cysteine; 3 mM) decreased relaxations promoted by NONO2P. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor (ODQ; 10 μM) nearly abolished the vasorelaxation. The cGMP-dependent protein kinase (PKG) inhibition (KT5823; 1 μM) attenuated the NONO2P relaxant effect. The vasorelaxant response was significantly attenuated by blocking inward rectifying K + channels (K ir ), voltage-operated K + channels (K V ), and large conductance Ca 2+ -activated K + channels (BK Ca ). NONO2P-induced relaxation was attenuated by cyclopiazonic acid (10 μM), indicating that sarcoplasmic reticulum Ca2+-ATPase (SERCA) activation is involved in this relaxation. Moreover, NONO2P increased NO levels in endothelial cells and cGMP production.
Conclusions: NONO2P induces vasorelaxation with the same magnitude as SNP, releasing NO • and NO - . Its vasorelaxant effect involves sGC, PKG, K + channels opening, and SERCA activation, suggesting its potential as a therapeutic option for CVD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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