Alterations in arterial CO2 rather than pH affect the kinetics of neurovascular coupling in humans

Abstract

Key points: We investigated the influence of arterial $P_{C{O}_2}$ ( $P_{\mathrm{aC}{O}_2}$ ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in $P_{\mathrm{aC}{O}_2}$ prior to and following intravenous NaHCO₃ to acutely elevate arterial pH and [HCO₃^- ]. The NVC response was not altered following NaHCO₃ between stepwise $P_{\mathrm{aC}{O}_2}$ stages; therefore, NVC is acutely mediated by $P_{\mathrm{aC}{O}_2}$ rather than the prevailing arterial [H⁺ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg $P_{\mathrm{aC}{O}_2}$ and the absolute peak change was reduced by -19% with +10 mmHg $P_{\mathrm{aC}{O}_2}$ irrespective of acutely elevated arterial pH/[HCO₃^- ]. The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively) likely indicating an influence of resting cerebrovascular tone on NVC responsiveness.

Abstract: Elevations in cerebral metabolism necessitate appropriate coordinated and localized increases in cerebral blood flow (i.e. neurovascular coupling; NVC). Recent pre-clinical work indicates that arterial $P_{C{O}_2}$ ( $P_{\mathrm{aC}{O}_2}$ ) mediates NVC independently of arterial/extracellular pH; this has yet to be experimentally tested in humans. The goal of this study was to investigate the hypotheses that: (1) the NVC response would be unaffected by acute experimentally elevated arterial pH; rather, $P_{\mathrm{aC}{O}_2}$ would regulate any changes in NVC; and (2) stepwise respiratory alkalosis and acidosis would each progressively reduce the NVC response. Ten healthy males completed a standardized visual stimulus-evoked NVC test during matched stepwise iso-oxic alterations in $P_{\mathrm{aC}{O}_2}$ (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following intravenous NaHCO₃ (8.4%, 50 mEq/50 ml) that elevated arterial pH (7.406 ± 0.019 vs. 7.457 ± 0.029; P < 0.001) and [HCO₃^- ] (26.2 ± 1.5 vs. 29.3 ± 0.9 mEq/l; P < 0.001). Although the NVC response was collectively attenuated by 27-38% with -10 mmHg $P_{\mathrm{aC}{O}_2}$ (stage post hoc: all P < 0.05), this response was unaltered following NaHCO₃ (all P > 0.05) irrespective of the higher pH (P = 0.002) at each matched stage of $P_{\mathrm{aC}{O}_2}$ (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg $P_{\mathrm{aC}{O}_2}$ irrespective of acutely elevated arterial pH/[HCO₃^- ] (stage post hoc: P = 0.022). The NVC kinetics (i.e. time to peak) were markedly slower with hypercapnia versus hypocapnia (24 ± 5 vs. 7 ± 5 s, respectively; stage effect: P < 0.001). Overall, these findings indicate that temporal patterns in NVC are acutely regulated by $P_{\mathrm{aC}{O}_2}$ rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.

Keywords: carbon dioxide; cerebral blood flow; humans; metabolic alkalosis; neurovascular coupling.