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.
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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.
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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.
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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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Menegatti, R., Carvalho, F.S., Lião, L.M. et al. Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1071–1083 (2019). https://doi.org/10.1007/s00210-019-01649-8
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DOI: https://doi.org/10.1007/s00210-019-01649-8