Acid-base regulation and sensing: Accelerators and brakes in metabolic regulation of cerebrovascular tone

Abstract

Metabolic regulation of cerebrovascular tone directs blood flow to areas of increased neuronal activity and during disease states partially compensates for insufficient perfusion by enhancing blood flow in collateral blood vessels. Acid-base disturbances frequently occur as result of enhanced metabolism or insufficient blood supply, but despite definitive evidence that acid-base disturbances alter arterial tone, effects of individual acid-base equivalents and the underlying signaling mechanisms are still being debated. H⁺ is an important intra- and extracellular messenger that modifies cerebrovascular tone. In addition, low extracellular [HCO₃^-] promotes cerebrovascular contraction through an endothelium-dependent mechanism. CO₂ alters arterial tone development via changes in intra- and extracellular pH but it is still controversial whether CO₂ also has direct vasomotor effects. Vasocontractile responses to low extracellular [HCO₃^-] and acute CO₂-induced decreases in intracellular pH can counteract H⁺-mediated vasorelaxation during metabolic and respiratory acidosis, respectively, and may thereby reduce the risk of capillary damage and cerebral edema that could be consequences of unopposed vasodilation. In this review, the signaling mechanisms for acid-base equivalents in cerebral arteries and the mechanisms of intracellular pH control in the arterial wall are discussed in the context of metabolic regulation of cerebrovascular tone and local perfusion.

Keywords: Cerebral blood flow; metabolism; neurovascular coupling; pH; penumbra.

Figure 1.

Schematic showing the major pathways for net cellular acid and base extrusion in the vascular wall. Net acid extrusion takes place via NBCn1-mediated Na⁺,HCO₃^–-cotransport and NHE1-mediated Na⁺/H⁺-exchange. Net base extrusion takes place primarily via Cl^–/HCO₃^–-exchange.

Figure 2.

Schematic showing known and putative sensors for H⁺ and HCO₃^– in the vascular wall, relationships to acid–base transporters, and relevant downstream signaling pathways for regulation of arterial tone. The Ca²⁺ and H⁺ buffers partially overlap, which allows acute changes in pH_i to change intracellular [Ca²⁺] and hence arterial tone. H⁺ has variable effects on different K⁺ conductances, with BK-channels inhibited and K_ATP-channels activated during intracellular acidification. Regulation of gap junction communication by pH_i is complex as some connexins are inhibited by both intracellular acidification and alkalinization.^,– BK: large-conductance Ca²⁺-activated K⁺-channel; CA: carbonic anhydrase; K_ATP: ATP-sensitive K⁺-channel; NOS: NO-synthase; PMCA: plasma membrane Ca²⁺-ATPase; VGCC: voltage-gated Ca²⁺-channels; V_m: membrane potential. The figure is adapted from Boedtkjer et al.; ©The International Union of Physiological Sciences and The American Physiological Society.