Phosphodiesterase inhibition restores hypoxia-induced cerebrovascular dysfunction subsequent to improved systemic redox homeostasis: A randomized, double-blind, placebo-controlled crossover study

Stacey, Benjamin S., Marley, Christopher J., Tsukamoto, Hayato, Dawkins, Tony G., Owens, Thomas S., Calverley, Thomas A., Fall, Lewis, Iannetelli, Angelo, Lewis, Ifan, Coulson, James M., Stembridge, Mike and Bailey, Damian M. 2025. Phosphodiesterase inhibition restores hypoxia-induced cerebrovascular dysfunction subsequent to improved systemic redox homeostasis: A randomized, double-blind, placebo-controlled crossover study. Journal of Cerebral Blood Flow & Metabolism 10.1177/0271678x251313747

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Abstract

To what extent sildenafil, a selective inhibitor of the type-5 phosphodiesterase modulates systemic redox status and cerebrovascular function during acute exposure to hypoxia remains unknown. To address this, 12 healthy males (aged 24 ± 3 y) participated in a randomized, placebo-controlled crossover study involving exposure to both normoxia and acute (60 min) hypoxia (Fi[Formula: see text] = 0.14), followed by oral administration of 50 mg sildenafil and placebo (double-blinded). Venous blood was sampled for the ascorbate radical (A•−: electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (NO: ozone-based chemiluminescence). Transcranial Doppler ultrasound was employed to determine middle cerebral artery velocity (MCAv), cerebral delivery of oxygen [Formula: see text] dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to hypo/hypercapnia (CVRCO2HYPO/HYPER). Cortical oxyhemoglobin (cO2Hb) and oxygenation index (OI) were assessed using pulsed continuous wave near infra-red spectroscopy. Hypoxia decreased total plasma NO ( P = 0.008), [Formula: see text] ( P = <0.001) and cO2Hb ( P = 0.005). In hypoxia, sildenafil selectively reduced A•− ( P = 0.018) and MCAV ( P = 0.018), and increased dCA metrics of low-frequency phase ( P = 0.029) and CVRCO2HYPER ( P = 0.007) compared to hypoxia-placebo. Collectively, these findings provide evidence for a PDE-5 inhibitory pathway that enhances select aspects of cerebrovascular function in hypoxia subsequent to a systemic improvement in redox homeostasis and independent of altered vascular NO bioavailability.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	SAGE Publications
ISSN:	0271-678X
Date of First Compliant Deposit:	12 May 2025
Date of Acceptance:	20 December 2024
Last Modified:	12 May 2025 14:30
URI:	https://orca.cardiff.ac.uk/id/eprint/176110

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