K_ATP channels modulate cerebral blood flow and oxygen delivery during isocapnic hypoxia in humans

Abstract

Key points ATP‐sensitive K+ (KATP) channels mediate hypoxia‐induced cerebral vasodilatation and hyperperfusion in animals. We tested whether KATP channels blockade affects the increase in human cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2) during hypoxia. Hypoxia‐induced increases in the anterior circulation and total cerebral perfusion were attenuated under KATP channels blockade affecting the relative changes of brain oxygen delivery. Therefore, in humans, KATP channels activation modulates the vascular tone in the anterior circulation of the brain, contributing to CBF and CDO2 responses to hypoxia. Abstract ATP‐sensitive K+ (KATP) channels mediate hypoxia‐induced cerebral vasodilatation and hyperperfusion in animals. We tested whether KATP channels blockade affects the increase in cerebral blood flow (CBF) and the maintenance of oxygen delivery (CDO2) during hypoxia in humans. Nine healthy men were exposed to 5‐min trials of normoxia and isocapnic hypoxia (IHX, 10% O2) before (BGB) and 3 h after glibenclamide ingestion (AGB). Mean arterial pressure (MAP), arterial saturation (SnormalaO2), partial pressure of oxygen (PnormalaO2) and carbon dioxide (PnormalaCO2), internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF), total (t)CBF (Doppler ultrasound) and CDO2 were quantified during the trials. IHX provoked similar reductions in SnormalaO2 and PnormalaO2, while MAP was not affected by oxygen desaturation or KATP blockade. A smaller increase in ICABF (ΔBGB: 36 ± 23 vs. ΔAGB 11 ± 18%, p = 0.019) but not in VABF (∆BGB 26 ± 21 vs. ∆AGB 27 ± 27%, p = 0.893) was observed during the hypoxic trial under KATP channels blockade. Thus, IHX‐induced increases in tCBF (∆BGB 32 ± 19 vs. ∆AGB 14 ± 13%, p = 0.012) and CDO2 relative changes (∆BGB 7 ± 13 vs. ∆AGB −6 ± 14%, p = 0.048) were attenuated during the AGB hypoxic trial. In a separate protocol, 6 healthy men (5 from protocol 1) underwent a 5‐min exposure to normoxia and IHX before and 3 h after placebo (5 mg of cornstarch) ingestion. IHX reduced SnormalaO2 and PnormalaO2, but placebo did not affect the ICABF, VABF, tCBF, or CDO2 responses. Therefore, in humans, KATP channels activation modulates vascular tone in the anterior rather than the posterior circulation of the brain, contributing to tCBF and CDO2 responses to hypoxia.

The middle cerebral artery blood velocity response to acute normobaric hypoxia occurs independently of changes in ventilation in humans

“…This response may be governed by local vasodilatory mechanisms (e.g. factors associated with the endothelium such as adenosine, nitric oxide and prostaglandins; Ainslie & Ogoh, 2010; Rocha et al., 2020). However, as a potential contribution from the secondary effects of an increase in ventilation might be possible we tested the hypothesis that enhanced ventilation independently increases MCA V mean during acute isocapnic hypoxia.…”

“…Isocapnic hypoxia increases internal carotid and vertebral artery blood flows (Ogoh et al., 2013), along with middle cerebral artery mean blood velocity (MCA V mean ) (Willie et al., 2012). It is possible that, in addition to the local vasodilatory effect of hypoxaemia (Kety & Schmidt, 1948; Rocha et al., 2020), the increase in ventilation contributes to the cerebral hyperaemic responses to isocapnic hypoxia. Indeed, the breathing changes that occur in hypoxia lead to changes in ventilation efficiency, blood oxygenation, systemic and pulmonary pressure (Bilo et al., 2012) – all with the potential to increase cerebral blood flow (Willie et al., 2014).…”

“…that, in addition to the local vasodilatory effect of hypoxaemia (Kety & Schmidt, 1948;Rocha et al, 2020), the increase in ventilation contributes to the cerebral hyperaemic responses to isocapnic hypo-…”

Scratching the surface of hypoxic cerebral vascular control: a potentially polarizing view of mechanistic research in humans

“…The study by Rocha et al . (2020) in this issue of The Journal of Physiology investigated the role of ATP‐sensitive K + (K ATP ) channels in the regulation of hypoxic cerebral vasodilatation in humans. The authors utilized duplex ultrasonography of the internal carotid and vertebral arteries to quantify CBF and radial artery catheterization to quantify arterial oxygen content during eupnoeic breathing and hypoxia.…”

“…Therefore, with regards to characterizing, in vivo, the various mechanisms implicated in the provocation of hypoxic cerebral vasodilatation in humans, it is pertinent to ask: have we been stuck scratching the surface? The study by Rocha et al (2020) in this issue of The Journal of Physiology investigated the role of ATP-sensitive K + (K ATP ) channels in the regulation of hypoxic cerebral vasodilatation in humans. The authors utilized duplex ultrasonography of the internal carotid and vertebral arteries to quantify CBF and radial artery catheterization to quantify arterial oxygen content during eupnoeic breathing and hypoxia.…”