Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation

Abstract

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p < 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.

Promising Cerebral Blood Flow Enhancers in Acute Ischemic Stroke

“…NO is a potential therapeutic agent for ischemic stroke and many experimental studies showed that exogenous NO, either via the administration of NO derivative [96,97] or by direct inhalation [98,99], increases CBF. An ideal vasodilating agent would selectively increase the diameter and/ or blood flow of the pial collateral blood vessels in the region of hypoperfused brain tissue, to extend the survivability of the salvageable tissue in the ischemic territory.…”

“…Below, we discuss the CBF-enhancing potential of NOindependent vasodilators. These fundamental research reports clarified the role and capabilities of NO during ischemic stroke and led to seminal reports on pre-clinically administered NO via direct inhalation or through NO donor agents to ameliorate the effect of brain ischemia [96][97][98][99].…”

Group‐based trajectory modeling of intracranial pressure in patients with acute brain injury: Results from multi‐center ICUs, 2008–2019

“…In cerebrovascular disease, high variations in ICPs remain a topic of concern, if unproperly treated, will be accompanied by hydrocephalus 27 . And researchers have employed machine learning to predict the trans‐stenotic pressure gradient in patients with idiopathic intracranial hypertension while others have used glyceryl trinitrate to decrease ICPs in ischemic stroke patients 28,29 . And in this paper, we focused on specific patients who are plagued by ABI.…”

“…27 And researchers have employed machine learning to predict the trans-stenotic pressure gradient in patients with idiopathic intracranial hypertension while others have used glyceryl trinitrate to decrease ICPs in ischemic stroke patients. 28,29 And in this paper, we focused on specific patients who are plagued by ABI. In this large cohort of ABI patients, GBTMs revealed six distinct ICP patterns over the ICU hospitalization period, adding nuance to time-invariant point values.…”

Specific subsystems of the inferior parietal lobule are associated with hand dysfunction following stroke: A cross‐sectional resting‐state fMRI study

“… 62 , 63 Fourth, the use of recently proposed imaging methods to evaluate cerebral edema formation 64 and microvasculature morphology 65 could help to supplement the neural mechanisms of hand dysfunction following acute to subacute stroke. Finally, imaging studies involving thrombectomy, 66 preclinical components (e.g., glyceryl trinitrate) 67 and thrombolytic drugs 68 after acute stroke have been limited; thus, it would be interesting to explore this new field in the future.…”