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 (Formula presented.) ((Formula presented.)) 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 (Formula presented.) (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 (Formula presented.), indicating that CBF is acutely regulated by (Formula presented.) rather than arterial pH. The cerebrovascular responses to changes in arterial H⁺/pH were altered in keeping with the altered relationship between (Formula presented.) 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 (Formula presented.) levels. Abstract: Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial (Formula presented.) ((Formula presented.)), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in (Formula presented.) 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 (Formula presented.) (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 (Formula presented.) (P = 0.927). Neither hypocapnic (3.44 ± 0.92 vs. 3.44 ± 1.05% per mmHg (Formula presented.); P = 0.499), nor hypercapnic (7.45 ± 1.85 vs. 6.37 ± 2.23% per mmHg (Formula presented.); P = 0.151) reactivity to (Formula presented.) 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 (Formula presented.) 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 (Formula presented.). These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by (Formula presented.) rather than arterial pH.