Vascular effects of the fetal hemoglobin inducer agent 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate
Data
2022-10-24
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MDPI
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Resumo
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-NG-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.
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