Indomethacin‐induced impairment of regional cerebrovascular reactivity: implications for respiratory control

Abstract

Cerebrovascular reactivity impacts CO₂-[H(+)] washout at the central chemoreceptors and hence has marked influence on the control of ventilation. To date, the integration of cerebral blood flow (CBF) and ventilation has been investigated exclusively with measures of anterior CBF, which has a differential reactivity from the vertebrobasilar system and perfuses the brainstem. We hypothesized that: (1) posterior versus anterior CBF would have a stronger relationship to central chemoreflex magnitude during hypercapnia, and (2) that higher posterior reactivity would lead to a greater hypoxic ventilatory decline (HVD). End-tidal forcing was used to induce steady-state hyperoxic (300 mmHg P ET ,O₂) hypercapnia (+3, +6 and +9 mmHg P ET ,CO₂) and isocapnic hypoxia (45 mmHg P ET ,O₂) before and following pharmacological blunting (indomethacin; INDO; 1.45 ± 0.17 mg kg(-1)) of resting CBF and reactivity. In 22 young healthy volunteers, ventilation, intra-cranial arterial blood velocities and extra-cranial blood flows were measured during these challenges. INDO-induced blunting of cerebrovascular flow responsiveness (CVR) to CO₂ was unrelated to variability in ventilatory sensitivity during hyperoxic hypercapnia. Further results in a sub-group of volunteers (n = 9) revealed that elevations of P ET,CO₂ via end-tidal forcing reduce arterial-jugular venous gradients, attenuating the effect of CBF on chemoreflex responses. During isocapnic hypoxia, vertebral artery CVR was related to the magnitude of HVD (R(2) = 0.27; P < 0.04; n = 16), suggesting that CO₂-[H(+)] washout from central chemoreceptors modulates hypoxic ventilatory dynamics. No relationships were apparent with anterior CVR. As higher posterior, but not anterior, CVR was linked to HVD, our study highlights the importance of measuring flow in posterior vessels to investigate CBF and ventilatory integration.

Comparing and characterizing transient and steady‐state tests of the peripheral chemoreflex in humans

“…Poulin & Robbins, 1998;Narkiewicz et al 2006;Steinback et al 2009;Hoiland et al 2015a). Last, we aimed to compare and correlate the magnitude of the HVRs elicited from the TT-N 2 test and the steady-state tests.…”

“…In addition, although the steady-state isocapnic hypoxia test maintains P ET,CO 2 close to eucapnic levels, a hypoxia-mediated increase in cerebral blood flow can theoretically increase CO 2 washout through cerebrovascular reactivity, subsequently clearing CO 2 from brainstem tissue, where central chemoreceptors reside (e.g. Ainslie & Duffin, 2009;Hoiland et al 2015a). Thus, central chemoreceptor activity may be depressed during isocapnic hypoxia and also dampen the HVR or the subsequent HVD (Poulin & Robbins, 1998;Hoiland et al 2015a).…”

“…Ainslie & Duffin, 2009;Hoiland et al 2015a). Thus, central chemoreceptor activity may be depressed during isocapnic hypoxia and also dampen the HVR or the subsequent HVD (Poulin & Robbins, 1998;Hoiland et al 2015a). Despite these possible confounders, steady-state tests using DEF have been widely adopted and are believed to isolate the peripheral chemoreceptors and the HVR (e.g.…”

“…hypoxic ventilatory decline; Powell et al 1998;Steinback & Poulin, 2007); (iii) concomitant cardiovascular and cerebrovascular responses (e.g. Poulin & Robbins, 1998;Steinback & Poulin, 2008;Ainslie & Duffin, 2009;Willie et al 2012;Hoiland et al 2015a); and (iv) the complex interactions between the central and peripheral chemoreceptors (Blain et al 2010;Cui et al 2012;Tin et al 2012;Duffin & Mateika, 2013;Teppema & Smith, 2013;Wilson & Day, 2013;Smith et al 2015).…”

The effects of superimposed tilt and lower body negative pressure on anterior and posterior cerebral circulations

“…), administration of indomethacin (Hoiland et al. ), and during changes in central blood volume such as during tilt (Tymko et al. ), thigh cuff release (Sato et al.…”