Vascular Effects of the Fetal Hemoglobin Inducer Agent 3-(1,3-Dioxoisoindolin-2-yl) Benzyl Nitrate.

Autor: Terroni B; School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara 14800-903, Brazil., de Moraes LHO; Department of Physiological Sciences, Federal University of São Carlos (UFSCar), São Carlos 13565-905, Brazil., Pavan AR; School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara 14800-903, Brazil.; Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, Brazil., Rodrigues GJ; Department of Physiological Sciences, Federal University of São Carlos (UFSCar), São Carlos 13565-905, Brazil., Dos Santos JL; School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara 14800-903, Brazil.; Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800-060, Brazil.
Jazyk: angličtina
Zdroj: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2022 Oct 24; Vol. 15 (11). Date of Electronic Publication: 2022 Oct 24.
DOI: 10.3390/ph15111311
Abstrakt: Vascular endothelium is a protective layer of cells lining the lumen of blood vessels that plays important roles by releasing factors responsible for controlling the vascular tone, regulating the expression of pro-inflammatory cytokines, and expressing adhesion molecules involved in vascular hemostasis. Imbalance of vascular properties leads to endothelial dysfunction (ED) and cardiovascular damage. Some diseases, such as sickle cell anemia, are characterized by ED with reduction in the levels of nitric oxide (NO). Previously, we have shown that the fetal hemoglobin inducer agent 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate ( Lapdesf-4c ) could act as NO donor, inhibiting platelet aggregation and reducing the inflammation associated with SCA. However, the vascular effect of this compound was not yet studied. Herein, we evaluated the effects of Lapdesf-4c in vascular reactivity experiments using aortic rings from male Wistar rats (300 g/90 days). We have found that Lapdesf-4c induced vasodilation in the presence (E+) or absence of endothelium (E-) with an average of EMax values of 101.8 ± 3.33% and 111.8 ± 3.21%. The mechanism of action was studied using 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), L -N G -nitroarginine methyl ester ( L -NAME), and hydroxocobalamin. The EMax values for those pathways were hydroxocobalamin (30.6 ± 2.21%), ODQ (4.75 ± 0.51%), and L -NAME (109 ± 3.65), suggesting that Lapdesf-4c exhibits NO-dependent mechanisms. Lapdesf-4c was able to prevent angiotensin-induced ED after incubation of aorta rings for 1 h. We found based on the concentration-effect curve using acetylcholine (ACh) that pEC50 values for the control, Ang II, and combination of (Ang II + Lapdesf-4c ) were 6.73, 6.46, and 7.15, respectively. In conclusion, Lapdesf-4c has emerged as a new drug candidate that can promote vasodilation and act as a protective agent against ED, being useful to prevent vascular damage.
Databáze: MEDLINE
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