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

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.