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

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acute experimental metabolic alkalosis on neurovascular coupling (NVC). We assessed stepwise iso-oxic alterations in PaCO2 prior to and following intravenous NaHCO3 to acutely elevate arterial pH and [HCO3- ]. The NVC response was not altered following NaHCO3 between stepwise PaCO2 stages; therefore, NVC is acutely mediated by PaCO2 rather than the prevailing arterial [H+ ]/pH. The NVC response was attenuated by 27-38% with -10 mmHg PaCO2 and the absolute peak change was reduced by -19% with +10 mmHg PaCO2 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 PCO2 ( PaCO2 ) 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, PaCO2 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 PaCO2 (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 PaCO2 (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 PaCO2 (P = 0.417). The absolute peak change was reduced by -19 ± 41% with +10 mmHg PaCO2 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 PaCO2 rather than arterial pH per se in the setting of acute metabolic alkalosis in humans.

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis.

KEY POINTS: We investigated the influence of arterial PCO2 ( PaCO2 ) with and without acutely elevated arterial pH and bicarbonate ([HCO3- ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in PaCO2 (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3- ) to acutely elevate arterial pH and [HCO3- ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of PaCO2 , indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between PaCO2 and H+ /pH following NaHCO3- infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3- infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3- independent of PaCO2 levels. ABSTRACT: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial PCO2 ( PaCO2 ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in PaCO2 or intravascular bicarbonate ([HCO3- ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in PaCO2 (hypocapnia: -5, -10 mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3- ; 8.4%, 50 mEq 50 mL-1 ) to elevate pH (7.408 ± 0.020 vs. 7.461 ± 0.030; P < 0.001) and [HCO3- ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L-1 ; P < 0.001). Absolute CBF was not different at each stage of CO2 reactivity (P = 0.629) following NaHCO3- , irrespective of a higher pH (P < 0.001) at each matched stage of PaCO2 (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg PaCO2 ; P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg PaCO2 ; P = 0.151) reactivity to PaCO2 were altered pre- to post-NaHCO3- . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P = 0.019) and hypercapnic CVR was lower (P = 0.025) following NaHCO3- , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between PaCO2 and arterial H+ /pH consequent to NaHCO3- . Lastly, CBF was higher (688 ± 105 vs. 732 ± 89 mL min-1 , 7% ± 12%; P = 0.047) following NaHCO3- during isocapnic breathing providing support for a direct influence of HCO3- on cerebrovascular tone independent of PaCO2 . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by PaCO2 rather than arterial pH.