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Cerebral Blood Flow Regulation (Carbon Dioxide, Oxygen, and Nitric Oxide)
Introduction
The effects of carbon dioxide (CO 2 ), oxygen (O 2 ), and nitric oxide (NO) on the cerebrovasculature are the most pronounced, easily demonstrated, and reproduced phenomena observed in the cerebral circulation. Studies in man and animals, using many different techniques, have shown that CO 2 , O 2 , and NO exert a profound influence on cerebral blood flow (CBF). Cerebral vasodilation to hypercapnia, hypoxia, and NO, and vasoconstriction to hypocapnia, hyperoxia, and NO inhibitors are universal findings in mammals, regardless of age or sex. Thus, these gases are considered to be fundamental regulators of CBF. Here I briefly review the effects of CO 2 , O 2 , and NO on the cerebral vasculature and the potential mechanisms of action which account for these effects.
Physiological Responses of CO 2
An increase in arterial CO 2 tension (PaCO 2 ) produces perhaps the most marked and consistent cerebral vasodilation of any known agent. In man, 5% CO 2 inhalation increases CBF by about 50%, and 7% CO 2 by 100% . It had been proposed that the CBF response to alterations in PaCO 2 was a threshold phenomenon; however, it was subsequently shown that this response is a continuous one ( Fig. 11.1 ). Furthermore, the CBF/PaCO 2 relationship can be described by an S-shaped curve. There also appears to be a maximal increase in CBF with hypercapnia. When PaCO 2 is altered from 4 to over 400 mmHg, a maximal increase in CBF occurs at about 150 mmHg. On the other hand, reducing PaCO 2 from about 45 to 25 mmHg reduces CBF by about 35%. These alterations in CBF with hyper- or hypocapnia are reversible.
Despite all cerebral vessels respond to changes in CO 2, hypercapnia dilates smaller cerebral arterioles more than larger ones, but the hypocapnic vasoconstriction effect is size independent. While the effects of hypercapnia are reversed when PaCO 2 is reduced, animals exposed to prolonged increases in PaCO 2 increase CBF initially; however, after many hours or days of exposure, CBF returns toward baseline despite continued elevated PaCO 2 . Men exposed to high altitude for 3–5 days have higher CBF than those at sea level, and prolonged hypercapnia reduces CBF responsiveness to acute alterations in PaCO 2 . Prolonged hypocapnia also alters CBF responsiveness to acute changes in PaCO 2. During prolonged hypocapnia CBF initially decreases but later increases toward baseline despite the continued lowered PaCO 2 .
Anesthetized animals exposed to concentrations of CO 2 respond to a lesser degree than conscious animals. This may, at least in part, be explained by the depressive effect of anesthetics on brain metabolism and CO 2 production. This effect may be due to effects of metabolism on tissue levels of PCO 2 because a reduction in O 2 consumption would likely decrease the amount of CO 2 that is generated and diffuses from brain tissue to the vessel wall. The question of whether alterations in PaCO 2 change CBF equally in all brain regions is controversial. Some investigators show no differences in CO 2 reactivity among brain regions and that blood flow to the hemispheres, brainstem, cerebellum, and medulla is altered by the same percentage per mmHg change in PaCO 2 . Others found that gray and white matter blood flow increased with hypercapnia; however, the white matter increase was less than the gray matter increase. Other brain regional areas such as the posterior pituitary and choroid plexus demonstrate minimal increases in flow with hypercapnia.
There appears to be a developmental difference in the CBF response to CO 2 , although in all age groups, CBF increases with increasing PaCO 2 . In both fetus and newborn, gray matter blood flow increases at PaCO 2 greater than 40 mmHg, but changes little at lower PaCO 2 levels. It has also been demonstrated that the change in CBF/PaCO 2 is higher in the newborn than in the fetus, and this suggests that the cerebrovascular response to CO 2 may not be completely developed at birth. This depressed CO 2 response in the fetus may be correlated with a difference in cerebral O 2 consumption (cerebral metabolic rate of O 2 , CMRO 2 ). However, when CBF responses are normalized for CMRO 2 , the increase in CBF is greatest in newborns, smaller in adults, and even smaller in fetuses. The reactivity of cerebral vessels in mid-gestational fetuses (sheep, 93 days) versus near-term fetuses (sheep, 133 days) is interesting. CBF and CMRO 2 increase threefold between 93 and 133 days of gestation. The CBF response to hypercapnia is greater at 133 days in mL/min/100 g of flow, but not as a percentage of baselines or as a ratio of CBF/CMRO 2 . Thus, CO 2 reactivity appears normal relative to metabolism by 93 days gestation. Old age may also affect the responses to CO 2 , and a decreased CBF responsiveness has been observed with increasing age in humans.
Mechanisms of Action of CO 2
Several mechanisms have been proposed to account for the effects of CO 2 on the cerebrovasculature: extracellular fluid [H + ], prostaglandins, NO, and neural pathways.
Extracellular Fluid [H + ] pH Hypothesis
The main mechanism of the potent effect of CO 2 on CBF is a local action on cerebral arteries mediated by extracellular fluid [H + ] . Marked changes in PaCO 2 and bicarbonate ion concentration of cerebrospinal fluid (CSF) do not affect pial arteriolar caliber unless a change in pH occurs. This demonstrates that molecular CO 2 and bicarbonate ion have no vasoactivity and that it is the [H + ] which is the important vasoactive agent. The cerebral vasodilation produced by hypercapnia can be completely counteracted by a change in extravascular PaCO 2 of the same magnitude but in the opposite direction. This indicates that local effects of CO 2 can explain the alterations in vascular caliber produced by PaCO 2 changes. The pH hypothesis regulation of the cerebrovasculature was originally described more than 50 years ago and states that the actions of CO 2 are mediated by direct effects of [H + ] on cerebrovascular smooth muscle. The [H + ] in the area of vascular muscle depends on bicarbonate concentration and PCO 2 of the extracellular fluid at that site. In turn, extracellular fluid PCO 2 depends on both PaCO 2 and PCO 2 in CSF. Since the blood–brain barrier (BBB) is impermeable to bicarbonate and [H + ], but freely permeable to CO 2 , when PaCO 2 increases, molecular CO 2 diffuses across the barrier to increase local PCO 2 of vascular muscle, reduces extracellular fluid pH, and produces vasodilation. The reverse occurs when PaCO 2 is decreased. This local nature of CO 2 control by [H + ] has been verified using ventriculocisternal perfusion techniques. Alteration of bicarbonate concentration in one lateral ventricle lowered caudate nucleus blood flow when bicarbonate increased and suppressed the increased flow when PaCO 2 was elevated compared to contralateral caudate blood flow .
Prostaglandins
Prostaglandins may be mediators of the CBF CO 2 response. Vasodilator prostanoids are important in vasodilation to hypercapnia in some species (gerbil, mice, rat, and baboon), but not in others (rabbits and cats). That prostanoids are important in hypercapnia comes from the observation that indomethacin, a cyclooxygenase inhibitor, decreases the CBF response to CO 2 inhalation in baboons . Others have shown a complete abolition of the CBF response to hypercapnia with indomethacin and with no alteration in CMRO 2 . In premature infants, indomethacin blunts the cerebrovascular response to hypercapnia, but while indomethacin affects CBF in man, administration of aspirin and indomethacin does not decrease control of CBF or attenuate the increase in CBF with hypercapnia. Other more specific cyclooxygenase inhibitors (AHR-5850-sodium amfenac) do not alter diameter of pial arterioles during normo- or hypercapnia. There may be interaction between the prostanoid system and NO production, with prostacyclin facilitating the release of NO. Thus, in species in which prostanoids act as mediators of hypercapnic vasodilation, inhibition of NO synthase may impair the cerebrovascular response to hypercapnia. The cerebral circulatory response to CO 2 may be gender specific, and it has been demonstrated that this response is altered more by indomethacin in women than in men. The response of cerebral vessels to CO 2 is universal among species; thus, it is curious that the prostaglandin mechanism of hypercapnic vasodilation is species dependent. For a response so prevalent, the mechanism of action is likely to be similar across species.
Nitric Oxide
NO is an important messenger involved in a wide variety of biological processes including regulation of the cerebral circulation. It plays a role in the maintenance of resting cerebrovascular tone and perhaps in evoked vasodilation. Since NO is a diffusible, short lived, highly reactive molecule, its effects have usually been inferred from studies of NO synthase (NOS) activity or inhibitors of this enzyme. Therefore, the importance of NO in the mechanism of hypercapnic cerebrovasodilation is somewhat unclear. However, a large number of studies have found that NOS inhibitors attenuate the increase in CBF with hypercapnia by 35–95%. Because cerebral vessels remain responsive to other vasodilator stimuli (papaverine, nitroprusside, hypotension, and hypoxia) after NOS inhibition, the absent or reduced CBF response to hypercapnia is not due to nonspecific reduction of cerebral vascular responsivity. However, the studies are limited because cerebral vascular resistance was not calculated and to determine whether cerebral vessels truly vasodilated this must be known. This is important because blood pressure increases considerably following administration of NOS inhibitors, and CBF is decreased. On the other hand, other investigators have found little or no attenuation of cerebral vasodilation to hypercapnia following NOS inhibition . Other data indicate that NO may play a small role in cerebral vasodilation to hypercapnia at moderate PaCO 2 levels (∼50 mmHg) but not at higher levels (70 mmHg). Recent data in early gestation (93 days) and near-term gestation (133 days) sheep fetuses demonstrate that NOS inhibition does not alter cerebrovascular reactivity to CO 2 .
The precise factors which account for these discrepant findings may involve species differences, methodological differences, dose of NOS inhibitor and consequent inhibition, timing of NOS inhibition relative to hypercapnia onset, anesthetic, degree of hypercapnia, and the failure to calculate cerebrovascular resistance which truly defines vasodilation or vasoconstriction. The fact is that in all species studied, hypercapnia leads to cerebral vasodilation and an increase in CBF, and NOS inhibition does not completely ablate CO 2 reactivity. Considering that there are region-specific responses to CO 2 within the brain, this likely means that there is more than one mechanism that accounts for the CO 2 -mediated vasodilation. At best it would appear that the role of NO in the mechanism of the cerebrovascular response to CO 2 is as a modulator. There is no doubt that the major mechanism is increased perivascular [H + ] during hypercapnia which reduces extracellular fluid pH and relaxes cerebral vascular smooth muscle. Other additional overlapping mechanisms involving NO or prostanoids are likely to involve reduced extracellular fluid pH. It is possible that increased extracellular fluid [H + ] increases NOS activity or prostanoid production and/or release. It is also possible that there are multiple mechanisms accounting for the effects of CO 2 on the cerebrovasculature.
Neural Pathways
While this mechanism is understudied, the available literature is conflicting. Years ago it was suggested that hypercapnia stimulates cholinergic vasodilator reflex pathways . Possibly, CO 2 exerts its effects on cerebral vessels via remote neural sites such as arterial chemoreceptors or brainstem vasomotor centers. In fact, the CBF response to CO 2 may be abolished or attenuated by a number of interventions: atropine administration, α -adrenergic blockade, arterial chemoreceptor denervation, vagal section, section of the seventh nerve, and certain brainstem lesions. There is also impressive evidence arguing against a neural role in the regulation of cerebral vessels by CO 2 . Atropine, α -adrenergic blockade, section of the seventh, ninth, and tenth nerves, and arterial chemoreceptor denervation do not alter the CBF response to CO 2 . This potential mechanism of action is controversial, and there is no convincing evidence of neural involvement in cerebrovascular responses to CO 2 .
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