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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 9, pp 1071–1083 | Cite as

Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects

  • Ricardo Menegatti
  • Flávio S. Carvalho
  • Luciano M. Lião
  • Bianca Villavicencio
  • Hugo Verli
  • Aline A. Mourão
  • Carlos H. Xavier
  • Carlos H. Castro
  • Gustavo R. Pedrino
  • Octavio L. Franco
  • Iransé Oliveira-Silva
  • Nicole M. Ashpole
  • Osmar Nascimento SilvaEmail author
  • Elson A. Costa
  • James O. FajemiroyeEmail author
Original Article
  • 161 Downloads

Abstract

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

Keywords

Choline analog Muscarinic receptor Nitric oxide synthase Sympathoinhibition 

Notes

Acknowledgements

This work was supported by CAPES, CNPq, FAPEG and FUNDECT. Osmar N. Silva holds a postdoctoral scholarship from the National Council of Technological and Scientific Development (CNPq) and Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT) – Brazil [300583/2016-8]. We thank Marcelo Rodrigues Martins (PhD) of the veterinary pharmacy section Universidade Federal de Goiás for providing anesthetics freely.

Author’s contribution

JOF, NMA and GRP: synthesis and chemical characterization of LQFM032. BV and HV: in silico assays. JOF, CHX, CHC, ONS, OLF, IOS: devising the research method/methodology used. AAM, EAC, CHX, CHC, GRP: conducting research, statistical analysis and calculations. RM, FSC, LML: devising the concept and assumptions of the article. All authors wrote the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Ethics Committee of the Federal University of Goiás (protocol #172/09) as compliant with Brazil law.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ricardo Menegatti
    • 1
  • Flávio S. Carvalho
    • 1
  • Luciano M. Lião
    • 2
  • Bianca Villavicencio
    • 3
  • Hugo Verli
    • 3
  • Aline A. Mourão
    • 4
  • Carlos H. Xavier
    • 4
  • Carlos H. Castro
    • 4
  • Gustavo R. Pedrino
    • 4
  • Octavio L. Franco
    • 5
  • Iransé Oliveira-Silva
    • 6
  • Nicole M. Ashpole
    • 7
  • Osmar Nascimento Silva
    • 5
    Email author
  • Elson A. Costa
    • 8
  • James O. Fajemiroye
    • 4
    • 6
    Email author
  1. 1.Faculty of PharmacyUniversidade Federal de GoiásGoiâniaBrazil
  2. 2.Chemistry InstituteUniversidade Federal de GoiásGoiâniaBrazil
  3. 3.Centro de BiotecnologiaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Department of PhysiologyUniversidade Federal de GoiásGoiâniaBrazil
  5. 5.S-Inova Biotech, Programa de Pós-graduação em BiotecnologiaUniversidade Católica Dom BoscoCampo GrandeBrazil
  6. 6.UniEvangélicaCentro Universitário de AnápolisAnápolisBrazil
  7. 7.Department of BioMolecular Sciences, Division of Pharmacology, School of PharmacyUniversity of MississippiUniversityUSA
  8. 8.Department of PhamacologyUniversidade Federal de GoiásGoiâniaBrazil

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