In Endothelial Cells, the Activation or Stimulation of Soluble Guanylyl Cyclase Induces the Nitric Oxide Production by a Mechanism Dependent of Nitric Oxide Synthase Activation

Martinelli, A.; Rodrigues, Carla Nascimento dos Santos; Moraes, Thiago Francisco de; Rodrigues, Gerson Jhonatan

doi:10.18433/jpps29578

Cited by 11 publications

(7 citation statements)

References 25 publications

(23 reference statements)

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“…The attenuated effect is due to the influence of endothelium on vascular tonus, which acted independently of the vasodilator mediator. Nitric oxide induces its synthesis, through the activation of GCs and accumulation of cGMP in endothelial cells [16]. Our data corroborated the study of vasodilation in the presence and absence of endothelium and demonstrated that Lapdesf-4c was effective to promote vasodilation in the absence of endothelium.…”

Section: Discussionsupporting

confidence: 88%

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

et al. 2022

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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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Section: Discussionsupporting

confidence: 88%

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

et al. 2022

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“…Both UVB irradiation and cutaneous barrier disruption increase NO release, 39,47,95 which can activate soluble guanylyl cyclase. 39,96 The latter can further increase NO production, 97 leading to amplification of NO levels, consequently resulting in increased oxidative stress. Conversely, inhibition of guanylyl cyclase accelerates permeability barrier recovery, while activation of guanylyl cyclase delays barrier recovery in tape-stripped skin.…”

Section: Barrier-disrupted Skinmentioning

confidence: 99%

Role of nitric oxide in regulating epidermal permeability barrier function

Man

Wakefield

Mauro

et al. 2021

Experimental Dermatology

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Nitric oxide (NO), a free radical molecule synthesized by nitric oxide synthases (NOS), regulates multiple cellular functions in a variety of cell types. These NOS, including endothelial NOS (eNOS), inducible NOS (iNOS) and neural NOS (nNOS), are expressed in keratinocytes. Expression levels of both iNOS and nNOS decrease with ageing, and insufficient NO has been linked to the development of a number of disorders such as diabetes and hypertension, and to the severity of atherosclerosis. Conversely, excessive NO levels can induce cellular oxidative stress, but physiological levels of NO are required to maintain the normal functioning of cells, including keratinocytes. NO also regulates cutaneous functions, including epidermal permeability barrier homeostasis and wound healing, through its stimulation of keratinocyte proliferation, differentiation and lipid metabolism. Topical applications of a diverse group of agents which generate nitric oxide (called NO donors) such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) can delay permeability barrier recovery in barrier-disrupted skin, but iNOS is still required for epidermal permeability barrier homeostasis. This review summarizes the regulatory role that NO plays in epidermal permeability barrier functions and the underlying mechanisms involved.

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“…Concerning sGC activators, a potential candidate is ataciguat (HMR1766), which preferentially binds to the oxidized state of sGC, increasing its enzymatic activity independently of NO release. Ataciguat induces NO production in endothelial cells [139], improves vascular functions in an animal model of heart failure [140], and reverses hemodynamic changes in experimental pulmonary hypertension [141]. The safety and effects of ataciguat are currently being assessed in two studies involving patients with mild to moderate CAVS.…”

Section: Future Perspectivesmentioning

confidence: 99%

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

Donato

Ferri

Lupo

et al. 2020

IJMS

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Calcific aortic valve stenosis (CAVS), the most common heart valve disease, is characterized by the slow progressive fibro-calcific remodeling of the valve leaflets, leading to progressive obstruction to the blood flow. CAVS is an increasing health care burden and the development of an effective medical treatment is a major medical need. To date, no effective pharmacological therapies have proven to halt or delay its progression to the severe symptomatic stage and aortic valve replacement represents the only available option to improve clinical outcomes and to increase survival. In the present report, the current knowledge and latest advances in the medical management of patients with CAVS are summarized, placing emphasis on lipid-lowering agents, vasoactive drugs, and anti-calcific treatments. In addition, novel potential therapeutic targets recently identified and currently under investigation are reported.

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In Endothelial Cells, the Activation or Stimulation of Soluble Guanylyl Cyclase Induces the Nitric Oxide Production by a Mechanism Dependent of Nitric Oxide Synthase Activation

Cited by 11 publications

References 25 publications

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

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

Role of nitric oxide in regulating epidermal permeability barrier function

Current Evidence and Future Perspectives on Pharmacological Treatment of Calcific Aortic Valve Stenosis

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