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

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 (FiO₂  = 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 (CDO₂), dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to hypo/hypercapnia (CVR_{CO2HYPO/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), CDO₂ (P = <0.001) and cO₂Hb (P = 0.005). In hypoxia, sildenafil selectively reduced A^•- (P = 0.018) and MCA V (P = 0.018), and increased dCA metrics of low-frequency phase (P = 0.029) and CVR_CO2HYPER (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.