| Autor: |
Menegatti R; Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO, 74605-170, Brazil., Carvalho FS; Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO, 74605-170, Brazil., Lião LM; Chemistry Institute, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil., Villavicencio B; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 91500-970, Brazil., Verli H; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 91500-970, Brazil., Mourão AA; Department of Physiology, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil., Xavier CH; Department of Physiology, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil., Castro CH; Department of Physiology, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil., Pedrino GR; Department of Physiology, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil., Franco OL; S-Inova Biotech, Programa de Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, 79117-900, Brazil., Oliveira-Silva I; UniEvangélica, Centro Universitário de Anápolis, Anápolis, GO, 75083-515, Brazil., Ashpole NM; Department of BioMolecular Sciences, Division of Pharmacology, School of Pharmacy, University of Mississippi, University, MS, 38677-1848, USA., Silva ON; S-Inova Biotech, Programa de Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, 79117-900, Brazil. osmar.silva@catolica.edu.br., Costa EA; Department of Phamacology, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil., Fajemiroye JO; Department of Physiology, Universidade Federal de Goiás, Goiânia, GO, 74001-970, Brazil. olulolo@yahoo.com.; UniEvangélica, Centro Universitário de Anápolis, Anápolis, GO, 75083-515, Brazil. olulolo@yahoo.com. |
| Abstrakt: |
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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