Carbon Dioxide and the Cerebral Circulation

Abstract

(Brian) Associate Professor.Dennis M. Fisher, M.D., EditorTHE arterial partial pressure of carbon dioxide (PaCO(2)) is an important regulator of the cerebral circulation, and a large body of literature describes this relation. This review summarizes the current state of knowledge of the effect of CO2on cerebral physiology, focusing first on mechanisms of CO2-induced alteration of vascular tone, then on the effect of CO2on cerebral vascular regulation, and finally on CO2manipulation in patient care.This section summarizes information regarding the site of action of CO2on the cerebral circulation and cellular mechanisms important in CO2-mediated changes in cerebral vascular tone. The CO2-mediated alteration of brain extracellular pH is the initial step leading to changes in vascular tone. The effect of pH on cerebral vascular tone is mediated by nitric oxide (NO), prostanoids, cyclic nucleotides, potassium channels, and intracellular calcium. Most data available support an important role for each of these mediators in the response of the cerebral circulation to CO2. However, contradictory data exist, and there is no comprehensive understanding of how these mediators interact to control cerebral vascular tone. Further, mechanisms differ in neonates and adults.Increased carbon dioxide tension (PCO2) relaxes cerebral arteries in vitro, which indicates that CO2can cause cerebral vascular relaxation independent of extravascular cells. [1,2]In vivo, cerebral arteries respond to highly localized perivascular alteration of PCO2and pH, which indicates that the mechanisms that affect cerebral vascular tone are localized to the area of the blood vessel wall. [3–5]Cellular elements that could contribute to the cerebral vascular response to CO2include vascular cells (endothelium and smooth muscle) and extravascular cells (perivascular nerves, parenchymal neurons, and glia). In adult animals, removal of the endothelium in vitro [1]or endothelial damage in vivo [6]does not alter the response of cerebral arteries to hypercapnia. This suggests that in adults the endothelium is not involved in the response to CO2. In neonates, however, the endothelium does contribute to cerebral vasodilatation during hypercapnia. [7,8]Tetrodotoxin, which blocks sodium channels and prevents neuronal depolarization, does not reduce CO2-mediated cerebral vasodilation, indicating that depolarization of perivascular nerves or parenchymal neurons is not important. [6,9]Selective destruction of cortical neurons also does not alter the cerebral vascular response to hypercapnia. [10]Although these data in adults suggest that the endothelium, parenchymal neurons, and perivascular nerves are not important during hypercapnia-induced cerebral vasodilation, it is also possible that these cells produce overlapping vasodilator messengers, and removal of an individual messenger is not sufficient to alter the response. No data exist regarding a potential role for glia in the CO2response of the cerebral circulation.In vitro data suggest that extravascular cells are not important in the response of cerebral arteries to increased PaCO(2). However, the relative contribution of vascular and extravascular cells to CO2-mediated vasodilation cannot be assessed by comparing in vivo and in vitro studies. Although isolated cerebral vessels relax with increased PCO2, technical differences between in vivo and in vitro studies make it impossible to know if vasodilation is equal in isolated vessels compared with in vivo blood vessels. Thus, in vivo, it is possible that dilation is larger, and some of the effect of CO2on cerebral vessels is mediated by extravascular cells.When cerebral vascular tone is altered by a change in PCO2, it is possible that CO2itself, a CO2-mediated change in pH, or both are signals leading to a change in vascular tone. Applying acidotic or alkalotic solutions to the brain dilates or constricts cerebral arteries in vivo, which indicates that pH can affect cerebral vascular tone. [4]In humans, Severinghaus et al. [11]showed that cerebral blood flow (CBF) was normal during chronic hypocapnia, which suggests that CO2itself does not alter cerebral vascular tone. Kontos et al. [3,12]offered the best evidence that pH rather than CO2is the controlling messenger for CO2-mediated alterations of cerebral vascular tone. Applying artificial cerebrospinal fluid (CSF) topically to the cerebral cortex of anesthetized cats, they showed that the diameter of cerebral arterioles responded only to changes in pH, regardless of fluid PCO2. During alterations of fluid PCO2, the pH of the artificial CSF was held constant by altering its bicarbonate concentration. Because CO2diffuses freely through cell membranes and bicarbonate does not, these data suggest that extracellular pH is more important than intracellular pH in altering cerebral vascular tone. Data in isolated cerebral arteries also indicate that extracellular pH is more important than intracellular pH in hypercapn