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.

Figure 1

Schematic experimental outline for CO₂ and O₂ perturbations pre-and post INDO using end-tidal forcing Test 1, hyperoxic hypercapnia involved a 1 min baseline stage and four subsequent stages (0, +3, +6, +9 Torr ). Dotted lines separate transition periods from steady-state end-tidal clamping. Test 2, isocapnic hypoxia had a 1 min baseline stage followed by 10 min of steady-state isocapnic hypoxia (+1 , 45 Torr ). HVR, HVD, and time to peak were calculated as shown in this figure. Subjects were then orally administered INDO, and the tests were repeated following 90 min.

Figure 2

Absolute cerebrovascular flow responsiveness to CO₂ during steady-state hyperoxic hypercapnia pre- and post INDO ○, individual values; ▪, mean values. Mean cerebrovascular data plotted against steady-state hypercapnia steps with end-tidal forcing (0, +3, +6 and +9 ). A, absolute MCAv responses pre- and post INDO (cm s^–1 (mmHg )⁻¹; n = 13); B, absolute PCAv responses pre- and post INDO (cm s^–1 (mmHg )⁻¹); C, absolute ICA responses pre- and post INDO (ml min^–1 (mmHg )⁻¹); D, absolute VA responses pre- and post INDO (ml min^–1 (mmHg )⁻¹). *Significant change from baseline post INDO administration (P < 0.05).

Figure 3

Pre- and post INDO central chemoreflex responsiveness to steady-state hypercapnia A, mean ventilatory data (n = 14) plotted against steady-state hypercapnia steps with end-tidal forcing (0, +3, +6 and +9 ). Mean central chemoreflex responsiveness to elevations in both (▪ and □) and (• and ○). Error bars represent one standard deviation. B, individual (□ and ○) and mean (▪ and •) ventilatory reactivity to elevations in (▪ and □) and (• and ○).

Figure 4

Relationship between the INDO-induced reduction in cerebrovascular CO₂ reactivity and variability in central chemoreflex CO₂ sensitivity pre- and post INDO Delta (Δ) values were calculated within-subject from absolute cerebrovascular and respiratory reactivity slopes (see Figs 2 and 3). A, ΔMCAv CO₂ reactivity plotted against Δ sensitivity, within-subject (n = 13). B, ΔPCAv CO₂ reactivity plotted against Δ sensitivity, within-subject (n = 14). C, ΔICA CO₂ reactivity plotted against ΔCCR reactivity, within-subject (n = 7). D, ΔVA CO₂ reactivity plotted against Δ sensitivity, within-subject (n = 12).

Figure 5

Absolute cerebrovascular flow responsiveness to hypoxia during steady-state isocapnic hypoxia pre- and post INDO ○, individual values; ▪, mean values. A, absolute VA responses pre- and post INDO (ml min^–1 (–%)⁻¹; n = 7); B, absolute ICA responses pre- and post INDO (ml min^–1 (–%)⁻¹; n = 7). C, absolute PCAv responses pre- and post INDO (cm s^–1 (–%)⁻¹; n = 14); D, absolute MCAv responses pre- and post INDO (cm s^–1 (–%)⁻¹; n = 13); *Significant change from baseline post INDO administration (P < 0.05).

Figure 6

Relationship between hypoxic ventilatory decline (HVD) and relative cerebrovascular flow responsiveness to hypoxia during steady-state isocapnic hypoxia A, in the VA; B, in the ICA; C, in the PCA; D, in the MCA. The relationship between HVD (calculated as the zenith minus the nadir of ventilation during hypoxia) and relative reactivity of all vessels is plotted with the regression line and R² value representing the relationship of the pooled pre- (•) and post-INDO (○) data.

Figure 7

A theoretical schematic representing the relationship between two fluid compartments separated by a semi permeable membrane When two fluid compartments separated by a semipermeable membrane are adjacent to one another, a square wave change in the concentration of a substance in one fluid compartment (C1) will be 95% equilibrated with the opposite compartment (C2) over three time constants. A time constant (τ) represents the time required for a volume of fluid equal to that of C1 to flow through C2 (e.g. if C1 is 500 ml, 1.5 l would have to flow through C2 to reach 95% equilibration). This model can be applied to the cerebral vasculature and brain tissue compartment to understand the effect of cerebrovascular CO₂ reactivity in producing varying stimuli to breathe despite the same value for (or ), as is seen in our placebo/INDO intervention. The major limitation of this model is that if we use C2 to represent arterial blood vessels proximal to the central chemoreceptors, and C1 to represent the tissue compartment where the central chemoreceptors reside, C1 is, in contrast to a steady-state, constantly producing CO₂ via metabolism. Therefore, a simple square wave change cannot be assumed between blood and tissue CO₂, but for simplicity we can assume that the relationship between arterial and tissue CO₂ resides somewhere on the dashed line, based upon the magnitude of flow and metabolic production of CO₂ at any given time. Assuming constant CO₂ production, higher flow would result in a rightward shift down the line, and an overall reduced blood to tissue gradient.

Figure 8

Arterial to jugular venous carbon dioxide gradients and ventilatory sensitivity during varying chemoreflex tests The change in pre- and post INDO (continuous and dotted lines, respectively) during hypercapnia as a function of steady-state fractional inspired CO₂ (Xie et al. 2006), rebreathing (Fan et al. 2010a), and end-tidal forcing methods of controlling (current study). The bottom panel represents the changes in − gradient expected using each method. A, for the steady-state method, the pre-INDO gradient data points (•) are calculated from Peebles et al. , while the post-INDO data points (○) are theoretical. As INDO-induced reductions in cerebrovascular CO₂ reactivity should reduce CO₂ washout, it is expected that is not reduced to as great an extent post INDO, keeping the − gradient larger than in the pre-INDO scenario and resulting in increased ventilatory sensitivity. B, during rebreathing, the gradient between and is theoretically eliminated (Read & Leigh, 1967) and is independent of reactivity and thus should be the same pre- (•) and post INDO (○). This latter notion is supported by no changes in ventilatory sensitivity pre- and post INDO using the rebreathing method (Fan et al. 2010a). C, similar to the rebreathing method, we found no change in ventilatory sensitivity pre- and post INDO with end-tidal forcing. The pre-INDO (•) data points represent the − gradient recorded from previously collected data in our laboratory, while post-INDO (○) points represent the likelihood that − gradient magnitude was unchanged, explaining the similar ventilatory sensitivity pre- and post INDO.