SUMMARY The mechanism by which the local effect of CO 2 on pial arterioles is exerted was examined in anesthetized cats equipped with a cranial window for the direct observation of the microcirculation of the parietal cortex. The dilation of pial arterioles in response to application of artificial cerebrospinal fluid with low pH was the same whether or not the Pco 2 of the solution was maintained in the normal range or markedly increased. The constriction of pial arterioles in response to application of artificial cerebrospinal fluid with high pH was the same whether or not the Pco 2 of the solution was maintained in the normal range or markedly decreased. Finally, pial arterioles did not change their caliber in response to application of cerebrospinal fluid with unchanged pH but markedly increased or decreased Pco 2 , or bicarbonate ion concentration. These results show that the action of CO 2 on cerebral vessels is exerted via changes in extracellular fluid pH and that molecular CO 2 and bicarbonate ions do not have independent vasoactivity on these vessels.IT HAS BEEN demonstrated that local hypercapnic acidosis, induced by exposure of the surface of the brain to gaseous carbon dioxide or by application of acid solutions, produces dilation of cerebral vessels, in the absence of change in arterial blood Pco 2 .'"° Conversely, application of alkaline solutions produces vasoconstriction.1 ' M This local effect of CO 2 has been traditionally considered to be the major mechanism of its action on cerebral blood vessels and it is generally believed to be mediated through change in extracellular fluid pH. 7 It has never been demonstrated definitely, however, whether or not this local action of CO 2 is mediated exclusively through a change in local pH, or whether or not CO 2 has an additional action dependent on molecular CO 2 or on bicarbonate ion concentration and independent of changes in pH. Although the view that CO 2 is acting through a change in local pH overwhelmingly predominates, 8 the experiments supporting it, e.g., those based on application of acid or alkaline solutions to the surface of the brain, do not exclude effects dependent on molecular CO 2 or bicarbonate ions. Transient application of small amounts of acid or alkali under these circumstances is bound to alter both the pH and the CO a tension in the vicinity of the blood vessels, since body fluids contain bicarbonate ions which would buffer the change in pH. One cannot be certain that the ensuing changes in vessel caliber or blood flow are due to the change in pH or in Pco 2 or to both changes.The present experiments were designed to evaluate the independent actions of separate changes in pH and changes in CO 2 tension in the vicinity of the pial vessels. MethodsEighteen cats were anesthetized with intravenous sodium pentobarbital (30 mg/kg). The animals were paralyzed with intravenous decamethonium bromide (1 mg/kg) and ventilated with a positive pressure respirator connected to a tracheostomy tube. Expired CO 2 concentration was monitored conti...

Methods for implatation of cranial windows for the direct observations of the pial microcirculation in experimental animals are described in detail. These techniques are suitable for both acute experiments in anesthetized animals and chronic implantation permitting several months of observation in awake animals. Experience over several years shows that these techniques have an acceptably low rate of failure, are low in cost and can easily be mastered in most laboratories. They make possible observation of the microcirculation and accurate measurement of the diameter of pial vessels, and permit study of the effects on the microcirculation of a variety of maneuvers and vasoactive agents which can be studied by direct application as well as by intravascular administration. Because they preserve the intergrity of the skull, the techniques permit study of the cerebral microcirculation under conditions closely approximating the normal environment of these vessels.

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The mechanism of action of hypoxia on cerebral blood vessels and its role in the regulation of the cerebral circulation were investigated in anesthetized cats. Arterial hypoxia produced marked cerebral arteriolar vasodilation, which was partially reversed by perfusing the space under the cranial window with artificial cerebrospinal fluid (CSF) containing 6-94% oxygen. More marked increase in the local supply of oxygen, via perfusion of the space under the cranial window with fluorocarbon FC-80 equilibrated with 100% oxygen, completely eliminated the vasodilation induced by arterial hypoxia. Fluorocarbon equilibrated with 100% N2 had no effect on the vasodilation. The vasodilation associated with hypotension was completely reversed by perfusion with fluorocarbon equilibrated with 100% oxygen and was unaffected by perfusion with fluorocarbon or CSF equilibrated with gas not containing oxygen. The vasodilation associated with Metrazole-induced seizures was partially reversed by perfusion with fluorocarbon containing oxygen. The results show that hypoxia dilated cerebral blood vessels entirely via a local mechanism, that hypoxia is the dominant mechanism involved in the vasodilation associated with hypotension, and that it is, at least partially, responsible for the vasodilation associated with seizures.

Summary. In 17 healthy men, beta-adrenergic blockade reduced significantly the tachycardia and the elevation of cardiac output associated with inhalation of 7.5% oxygen for 7 to 10 minutes.Hypoxia did not increase plasma concentrations of epinephrine or norepinephrine in six subjects. Furthermore, blockade of alpha and beta receptors in the forearm did not modify the vasodilation in the forearm induced by hypoxia, providing pharmacologic evidence that hypoxia of the degree and duration used was not associated with an increase in the concentrations of circulating catecholamines in man.Part of the increase in cardiac output and heart rate during acute hypoxia in man is produced by stimulation of beta-adrenergic receptors, probably by cardiac sympathetic nerves. The mechanism of the vasodilation in the forearm during hypoxia remains uncertain.