Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases

Abstract

Within the family of endogenous gasotransmitters, nitric oxide (NO) is the smallest gaseous intercellular messenger involved in the modulation of several processes, such as blood flow and platelet aggregation control, essential to maintain vascular homeostasis. NO is produced by nitric oxide synthases (NOS) and its effects are mediated by cGMP-dependent or cGMP-independent mechanisms. Growing evidence suggests a crosstalk between the NO signaling and the occurrence of oxidative stress in the onset and progression of vascular diseases, such as hypertension, heart failure, ischemia, and stroke. For these reasons, NO is considered as an emerging molecular target for developing therapeutic strategies for cardio- and cerebrovascular pathologies. Several natural derived compounds, such as polyphenols, are now proposed as modulators of NO-mediated pathways. The aim of this review is to highlight the experimental evidence on the involvement of nitric oxide in vascular homeostasis focusing on the therapeutic potential of targeting NO with some natural compounds in patients with vascular diseases.

Storage Stability of Dietary Nitrate and Phenolic Compounds in Beetroot (Beta vulgaris) and Arugula (Eruca sativa) Juices

“…Blood flow, platelet aggregation, and vascular tone are all modulated via NO; hence, its impairment in the vascular system is associated with cardiovascular diseases (Forte et al, 2016). Due to its importance, approaches to enhance NO production and bioavailability for its use as a therapeutic agent have been a prominent area of research (Forte et al, 2016). Dietary nitrate and polyphenolic compounds present in fruits and vegetables are involved in supplementing and enhancing NO-producing pathways (Bondonno, Croft, Ward, Considine, & Hodgson, 2015;Duarte, Francisco, & Perez-Vizcaino, 2014).…”

Endothelium at a Glance

“…Besides noradrenaline, that binds on various adrenoceptors on endothelial cells and VSMC, other transmitters (such as adenosine triphosphate (ATP), calcitonin gene-related peptide (CGRP) acetylcholine (ACh), and neuropeptide Y) are released from nerve varicosities, thereby profoundly modulating endothelial function. Noradrenaline was shown to activate β 3 -adrenergic receptors on endothelium, thereby increasing NO production [89,90], while the co-transmitted ATP mediates endothelial hyperpolarization by acting on endothelial purinoceptors (P2Y) [88]; both effects finally induce vasorelaxation and, respectively, modulate the "classical" sympathetic vasoconstrictor effects on VSMC. Moreover, NO affects neurotransmission at the level of blood vessels, acting on presynaptic α 2 -adrenergic receptors, and it also interferes with the sympathetic neurotransmission in the central nervous system [87].…”

“…Of note is the dual role of eNOS: when the bioavailability of its substrates and/or cofactors is reduced and in conditions of increased oxidative stress, eNOS can get uncoupled and produces superoxide anion (O 2− ) instead of NO; O 2− is a highly reactive radical which forms peroxynitrite (ONOO − ) with NO, and in this way, it additionally decreases the bioavailability of NO and contributes to endothelial dysfunction [43,44,90].…”

“…NO exerts other effects: it inhibits platelet aggregation (interestingly, activated-plateletderived substances increase the activity of eNOS, thus producing more NO) and the adhesion of leucocytes to the vascular wall by decreasing the expression of adhesion molecules on endothelial surface [90]. Moreover, it interferes with cellular metabolism [125] by modulating mitochondrial function, and oxygen metabolism [106,126].…”

“…Therefore, the biosynthetic pathways of NO and its downstream targets might all represent potential therapeutic targets [90,131].…”