Ascorbate attenuates red light mediated vasodilation: Potential role of S-nitrosothiols

Abstract

There is significant therapeutic advantage of nitric oxide synthase (NOS) independent nitric oxide (NO) production in maladies where endothelium, and thereby NOS, is dysfunctional. Electromagnetic radiation in the red and near infrared region has been shown to stimulate NOS-independent but NO-dependent vasodilation, and thereby has significant therapeutic potential. We have recently shown that red light induces acute vasodilatation in the pre-constricted murine facial artery via the release of an endothelium derived substance. In this study we have investigated the mechanism of vasodilatation and conclude that 670 nm light stimulates vasodilator release from an endothelial store, and that this vasodilator has the characteristics of an S-nitrosothiol (RSNO). This study shows that 670 nm irradiation can be used as a targeted and non-invasive means to release biologically relevant amounts of vasodilator from endothelial stores. This raises the possibility that these stores can be pharmacologically built-up in pathological situations to improve the efficacy of red light treatment. This strategy may overcome eNOS dysfunction in peripheral vascular pathologies for the improvement of vascular health.

Electromagnetic energy (670 nm) stimulates vasodilation through activation of the large conductance potassium channel (BKCa)

“…R/NIR stimulated vasodilation was previously tested with the mouse facial artery, a surrogate for microvascular function. Consistent with previous observations, there was a 14.2% (±0.81) increase in vessel diameter after 5 min of light exposure to pre-constricted facial arteries ( Fig 1A ) [ 16 , 17 ]. Since potassium channels are key mediators of vasodilation, we tested the impact of channel inhibition on NIR vasodilation.…”

“…The effect plateaued when light was removed and then increased upon re-stimulation with light. There was no significant difference in the magnitude of R/NIR vasodilation in femoral vessels when compared to the facial artery in Fig 1 or previously published observations [ 16 , 17 ]. Patch clamp K + channel current recording from freshly dissociated mouse femoral arterial muscle cells using symmetrical K + (145 mM) recording solutions revealed existence of a 273 pS single K + channel current that displayed voltage-dependent increased openings and sensitivity to inhibition by the selective large conductance Ca 2+ -activated K + channel (BK Ca ) antagonist paxilline (1 μM) ( Fig 3A–3C ).…”

“…There is growing evidence that R/NIR increases NO levels through its action on these compounds. Previously we identified the action of light on S-nitrosothiol compounds, a potential NO source [ 17 ]. We have also described the ability of light to release NO from nitrosyl-hemoglobin and nitrosyl-myoglobin in the blood and cardiac tissue [ 14 ].…”

“…The mechanism of NO generation by R/NIR is independent of functional nitric oxide synthases, which increases its clinical relevance since many patients with PAD have impaired NOS function. Recently, we have shown R/NIR to stimulate vasodilation of physiologically pressurized external carotid vessels in mice through a NO and endothelial dependent manner, which differs from previously reported light stimulated vasodilation studies where vasodilation required inhibition of the small and intermediate potassium channels [13,16,17]. Unlike these studies which rely on pharmacological inhibitors of the NO pathway, we sought to characterize the effect of R/NIR on smooth muscle cell ion channel activity.…”

Ligustilide Prevents Radiation Enteritis by Targeting Gch1/BH4/eNOS to Improve Intestinal Ischemia

“…In our previous studies, we found that targeting the downregulation of GTP-cyclohydrolase 1 caused by IR to prevent endothelial dysfunction could be a new strategy for the prevention of RE (Yan et al, 2020). Gch1 is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the content of which plays an important role in maintaining endothelial NOS function, producing NO and maintaining vasodilation (Douglas et al, 2018b;Keszler et al, 2019). However, there is a lack of drugs that can improve this reduction in Gch1 observed after IR.…”