Inhaled nitric oxide protects cerebral autoregulation through prevention of impairment of ATP and calcium sensitive K channel mediated cerebrovasodilation after traumatic brain injury

Pastor, Philip; Curvêllo, Victor Prado; Hekierski, Hugh; Armstead, William M.

doi:10.1016/j.brainres.2019.01.008

Cited by 14 publications

(5 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings align with previous studies in adults which show that sildenafil treatment does not change the overall CBF ( Diomedi et al, 2005 ; Rosengarten et al, 2006 ; Al-Amran et al, 2012 ; Jahshan et al, 2017 ; Lindberg et al, 2017 ). However, in contrast to studies of rat pups ( Charriaut-Marlangue et al, 2012 ) or piglets ( Pastor et al, 2019 ) with induced brain injury in which iNO treatment leads to cerebral vasodilation and restores CBF, our preterm lambs (without prior brain injury) did not show any significant change of cerebral haemodynamics following iNO. Possibly, iNO may have selective actions depending on the presence of brain injury.…”

Section: Discussioncontrasting

confidence: 99%

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs is enhanced following sildenafil and inhaled nitric oxide administration

et al. 2023

View full text Add to dashboard Cite

Background: Neurovascular coupling (NVC) leads to an increase in local cerebral blood flow and oxygenation in response to increased neural activity and metabolic demand. Impaired or immature NVC reported in the preterm brain, potentially reduces cerebral oxygenation following increased neural activity, predisposing to cerebral tissue hypoxia. Endogenous nitric oxide (NO) is a potent vasodilator and a major mediator of NVC and the cerebral haemodynamic response. NO modulators, such as inhaled nitric oxide (iNO) and sildenafil, induce vasodilation and are used clinically to treat pulmonary hypertension in preterm neonates. However, their impact on NVC in the preterm brain are unknown. We aimed to characterise the cerebral functional haemodynamic response in the preterm brain exposed to NO modulators. We hypothesized that iNO and sildenafil in clinical dosages would increase the baseline cerebral perfusion and the cerebral haemodynamic response to neural activation.Methods: Preterm lambs (126–7 days’ gestation) were delivered and mechanically ventilated. The cerebral functional haemodynamic response was measured using near infrared spectroscopy as changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb), following left median nerve stimulations of 1.8, 4.8, and 7.8 s durations in control preterm lambs (n = 11), and following 4.8 and 7.8 s stimulations in preterm lambs receiving either sildenafil citrate (n = 6, 1.33 mcg/kg/hr) or iNO (n = 8, 20 ppm).Results: Following 1.8, 4.8, and 7.8 s stimulations, ∆oxyHb in the contralateral cortex increased (positive functional response) in 7/11 (64%), 7/11 (64%), and 4/11 (36%) control lambs respectively (p < 0.05). Remaining lambs showed decreased ΔoxyHb (negative functional response). Following 4.8 s stimulations, more lambs receiving sildenafil or iNO (83% and 100% respectively) showed positive functional response compared to the controls (p < 0.05). No significant difference between the three groups was observed at 7.8 s stimulations.Conclusion: In the preterm brain, prolonged somatosensory stimulations increased the incidence of negative functional responses with decreased cerebral oxygenation, suggesting that cerebral oxygen delivery may not match the oxygen demand. Sildenafil and iNO increased the incidence of positive functional responses, potentially enhancing NVC, and cerebral oxygenation.

show abstract

Section: Discussioncontrasting

confidence: 99%

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs is enhanced following sildenafil and inhaled nitric oxide administration

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Since iNO blocked upregulation of IL-6 after fluid percussion brain injury (Curvello et al 2018), it was postulated that iNO achieves brain protection via block of the sequential release of ET-1, ERK MAPK, and IL-6 ( Fig 1). Since cerebral autoregulation impairment and brain histopathology results from blockade of K channel function after TBI (Armstead and Vavilala 2014), it is speculated that iNO ultimately achieves brain protection after TBI via block of impairment of K channel function (Pastor et al 2019) (Fig 1). However, a caveat to these studies is that the time window for study is short (within 6h of FPI).…”

Section: Inhaled Nitric Oxide Improves Outcome In Preclinical Experimmentioning

confidence: 99%

Translational approach towards determining the role of cerebral autoregulation in outcome after traumatic brain injury

Armstead

Vavilala

2019

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

Cerebral autoregulation is impaired after traumatic brain injury (TBI), contributing to poor outcome. In the context of the neurovascular unit, cerebral autoregulation contributes to neuronal cell integrity and clinically Glasgow Coma Scale is correlated to intactness of autoregulation after TBI. Cerebral Perfusion Pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP) and thereby limit impairment of cerebral autoregulation and neurological deficits. However, current vasoactive agent choice used to elevate MAP to increase CPP after TBI is variable. Vasoactive agents, such as phenylephrine, dopamine, norepinephrine, and epinephrine, clinically have not sufficiently been compared regarding effect on CPP, autoregulation, and survival after TBI. The cerebral effects of these clinically commonly used vasoactive agents are incompletely understood. This review will describe translational studies using a more human like animal model (the pig) of TBI to identify better therapeutic strategies to improve outcome post injury. These studies also investigated the role of age and sex in outcome and mechanism(s) involved in improvement of outcome in the setting of TBI. Additionally, this review considers use of inhaled nitric oxide as a novel neuroprotective strategy in treatment of TBI.

show abstract

“…Despite its short half-life, NO has essential biological roles in vasodilation, mitochondrial biogenesis, anti-inflammation, and glucose uptake. ,− The decreased NO bioavailability is associated with aging and cardiometabolic syndrome, including insulin resistance, diabetes, atherosclerosis, heart failure, and dementia. ,− There have been various efforts to supplement exogenous NO-related agents, including l -arginine, NO inhalation, other NO donors, and phosphodiesterase-5 (PDE-5) inhibitors . Supplementing exogenous NO improves cardiovascular and neuronal functions. ,,− Although the previously reported reagents have some positive effects, most of the reagents are used for acute injuries, including stroke, hemorrhage, trauma, and encephalopathy . PDE-5 inhibitors have vasodilatory effects and reduce the damage from cerebral infarction and hemorrhage, but another study shows no effect on brain perfusion .…”

Section: Discussionmentioning

confidence: 99%

Subcutaneous Administration of a Nitric Oxide-Releasing Nanomatrix Gel Ameliorates Obesity and Insulin Resistance in High-Fat Diet-Induced Obese Mice

Ren

Hwang

Millican

et al. 2022

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

Nitric oxide (NO) is a gaseous signaling molecule, which plays crucial roles in various biological processes, including inflammatory responses, metabolism, cardiovascular functions, and cognitive function. NO bioavailability is reduced with aging and cardiometabolic disorders in humans and rodents. NO stimulates the metabolic rate by increasing the mitochondrial biogenesis and brown fat activation. Therefore, we propose a novel technology of providing exogenous NO to improve the metabolic rate and cognitive function by promoting the development of brown adipose tissue. In the present study, we demonstrate the effects of the peptide amphiphiles–NO-releasing nanomatrix gel (PANO gel) on high-fat diet-induced obesity, insulin resistance, and cognitive functions. Eight-week-old male C57BL/6 mice were subcutaneously injected in the brown fat area with the PANO gel or vehicle (PA gel) every 2 weeks for 12 weeks. The PANO gel-injected mice gained less body weight, improved glucose tolerance, and decreased fasting serum insulin and leptin levels compared with the PA gel-injected mice. Insulin signaling in the muscle, liver, and epididymal white adipose tissue was improved by the PANO gel injection. The PANO gel reduced inflammation, increased lipolysis in the epididymal white adipose tissue, and decreased serum lipids and liver triglycerides. Interestingly, the PANO gel stimulated uncoupled protein 1 gene expression in the brown and beige fat tissues. Furthermore, the PANO gel increased the cerebral blood flow and improved learning and memory abilities. Our results suggest that using the PANO gel to supply exogenous NO is a novel technology to treat metabolic disorders and cognitive dysfunctions.

show abstract

Inhaled nitric oxide protects cerebral autoregulation through prevention of impairment of ATP and calcium sensitive K channel mediated cerebrovasodilation after traumatic brain injury

Cited by 14 publications

References 16 publications

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs is enhanced following sildenafil and inhaled nitric oxide administration

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs is enhanced following sildenafil and inhaled nitric oxide administration

Translational approach towards determining the role of cerebral autoregulation in outcome after traumatic brain injury

Subcutaneous Administration of a Nitric Oxide-Releasing Nanomatrix Gel Ameliorates Obesity and Insulin Resistance in High-Fat Diet-Induced Obese Mice

Contact Info

Product

Resources

About